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  • Artemisinin‐derived antimalarial endoperoxides from bench‐side to bed‐side: Chronological advancements and future challenges
    Med. Res. Rev. (IF 9.791) Pub Date : 2020-01-12
    Mohit K. Tiwari; Sandeep Chaudhary

    According to WHO World Malaria Report (2018), nearly 219 million new cases of malaria occurred and a total no. of 435 000 people died in 2017 due to this infectious disease. This is due to the rapid spread of parasite‐resistant strains. Artemisinin (ART), a sesquiterpene lactone endoperoxide isolated from traditional Chinese herb Artemisia annua, has been recognized as a novel class of antimalarial drugs. The 2015 “Nobel Prize in Physiology or Medicine” was given to Prof Dr Tu Youyou for the discovery of ART. Hence, ART is termed as “Nobel medicine.” The present review article accommodates insights from the chronological advancements and direct statistics witnessed during the past 48 years (1971‐2019) in the medicinal chemistry of ART‐derived antimalarial endoperoxides, and their clinical utility in malaria chemotherapy and drug discovery.

  • Machine intelligence in peptide therapeutics: A next‐generation tool for rapid disease screening
    Med. Res. Rev. (IF 9.791) Pub Date : 2020-01-10
    Shaherin Basith; Balachandran Manavalan; Tae Hwan Shin; Gwang Lee

    Discovery and development of biopeptides are time‐consuming, laborious, and dependent on various factors. Data‐driven computational methods, especially machine learning (ML) approach, can rapidly and efficiently predict the utility of therapeutic peptides. ML methods offer an array of tools that can accelerate and enhance decision making and discovery for well‐defined queries with ample and sophisticated data quality. Various ML approaches, such as support vector machines, random forest, extremely randomized tree, and more recently deep learning methods, are useful in peptide‐based drug discovery. These approaches leverage the peptide data sets, created via high‐throughput sequencing and computational methods, and enable the prediction of functional peptides with increased levels of accuracy. The use of ML approaches in the development of peptide‐based therapeutics is relatively recent; however, these techniques are already revolutionizing protein research by unraveling their novel therapeutic peptide functions. In this review, we discuss several ML‐based state‐of‐the‐art peptide‐prediction tools and compare these methods in terms of their algorithms, feature encodings, prediction scores, evaluation methodologies, and software utilities. We also assessed the prediction performance of these methods using well‐constructed independent data sets. In addition, we discuss the common pitfalls and challenges of using ML approaches for peptide therapeutics. Overall, we show that using ML models in peptide research can streamline the development of targeted peptide therapies.

  • Cover Image, Volume 40, Issue 1
    Med. Res. Rev. (IF 9.791) Pub Date : 2019-12-17
    MeiHua Wan; Bo Ning; Sarah Spiegel; Christopher J. Lyon; Tony Y. Hu
  • Back Cover Image, Volume 40, Issue 1
    Med. Res. Rev. (IF 9.791) Pub Date : 2019-12-17
    Meichen Guo; Hang Song; Kai Li; Minchao Ma; Yang Liu; Qiang Fu; Zhonggui He
  • Tissue engineering strategies combining molecular targets against inflammation and fibrosis, and umbilical cord blood stem cells to improve hampered muscle and skin regeneration following cleft repair
    Med. Res. Rev. (IF 9.791) Pub Date : 2019-05-18
    Michaël Schreurs; C. Maarten Suttorp; Henricus A.M Mutsaers; Anne Marie Kuijpers‐Jagtman; Johannes W. Von den Hoff; Edwin M. Ongkosuwito; Paola L. Carvajal Monroy; Frank A.D.T.G. Wagener

    Cleft lip with or without cleft palate is a congenital deformity that occurs in about 1 of 700 newborns, affecting the dentition, bone, skin, muscles and mucosa in the orofacial region. A cleft can give rise to problems with maxillofacial growth, dental development, speech, and eating, and can also cause hearing impairment. Surgical repair of the lip may lead to impaired regeneration of muscle and skin, fibrosis, and scar formation. This may result in hampered facial growth and dental development affecting oral function and lip and nose esthetics. Therefore, secondary surgery to correct the scar is often indicated. We will discuss the molecular and cellular pathways involved in facial and lip myogenesis, muscle anatomy in the normal and cleft lip, and complications following surgery. The aim of this review is to outline a novel molecular and cellular strategy to improve musculature and skin regeneration and to reduce scar formation following cleft repair. Orofacial clefting can be diagnosed in the fetus through prenatal ultrasound screening and allows planning for the harvesting of umbilical cord blood stem cells upon birth. Tissue engineering techniques using these cord blood stem cells and molecular targeting of inflammation and fibrosis during surgery may promote tissue regeneration. We expect that this novel strategy improves both muscle and skin regeneration, resulting in better function and esthetics after cleft repair.

  • A new approach to developing diagnostics and therapeutics: Aggregation‐induced emission‐based fluorescence turn‐on
    Med. Res. Rev. (IF 9.791) Pub Date : 2019-05-09
    Meichen Guo; Hang Song; Kai Li; Minchao Ma; Yang Liu; Qiang Fu; Zhonggui He

    Fluorescence imaging is a promising visualization tool and possesses the advantages of in situ response and facile operation; thus, it is widely exploited for bioassays. However, traditional fluorophores suffer from concentration limits because they are always quenched when they aggregate, which impedes applications, especially for trace analysis and real‐time monitoring. Recently, novel molecules with aggregation‐induced emission (AIE) characteristics were developed to solve the problems encountered when using traditional organic dyes, because these new molecules exhibit weak or even no fluorescence when they are in free movement states but emit intensely upon the restriction of intramolecular motions. Inspired by the excellent performances of AIE molecules, a substantial number of AIE‐based probes have been designed, synthesized, and applied to various fields to fulfill diverse detection tasks. According to numerous experiments, AIE probes are more practical than traditional fluorescent probes, especially when used in bioassays. To bridge bioimaging and materials engineering, this review provides a comprehensive understanding of the development of AIE bioprobes. It begins with a summary of mechanisms of the AIE phenomenon. Then, the strategies to realize accurate detection using AIE probes are discussed. In addition, typical examples of AIE‐active materials applied in diagnosis, treatment, and nanocarrier tracking are presented. In addition, some challenges are put forward to inspire more ideas in the promising field of AIE‐active materials.

  • Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis
    Med. Res. Rev. (IF 9.791) Pub Date : 2019-05-27
    Ya‐Long Feng; Dan‐Qian Chen; Nosratola D. Vaziri; Yan Guo; Ying‐Yong Zhao

    Tissue fibrosis and cancer both lead to high morbidity and mortality worldwide; thus, effective therapeutic strategies are urgently needed. Because drug resistance has been widely reported in fibrotic tissue and cancer, developing a strategy to discover novel targets for targeted drug intervention is necessary for the effective treatment of fibrosis and cancer. Although many factors lead to fibrosis and cancer, pathophysiological analysis has demonstrated that tissue fibrosis and cancer share a common process of epithelial‐mesenchymal transition (EMT). EMT is associated with many mediators, including transcription factors (Snail, zinc‐finger E‐box‐binding protein and signal transducer and activator of transcription 3), signaling pathways (transforming growth factor‐β1, RAC‐α serine/threonine‐protein kinase, Wnt, nuclear factor‐kappa B, peroxisome proliferator‐activated receptor, Notch, and RAS), RNA‐binding proteins (ESRP1 and ESRP2) and microRNAs. Therefore, drugs targeting EMT may be a promising therapy against both fibrosis and tumors. A large number of compounds that are synthesized or derived from natural products and their derivatives suppress the EMT by targeting these mediators in fibrosis and cancer. By targeting EMT, these compounds exhibited anticancer effects in multiple cancer types, and some of them also showed antifibrotic effects. Therefore, drugs targeting EMT not only have both antifibrotic and anticancer effects but also exert effective therapeutic effects on multiorgan fibrosis and cancer, which provides effective therapy against fibrosis and cancer. Taken together, the results highlighted in this review provide new concepts for discovering new antifibrotic and antitumor drugs.

  • Lipoprotein‐associated phospholipase A2: The story continues
    Med. Res. Rev. (IF 9.791) Pub Date : 2019-05-29
    Fubao Huang; Kai Wang; Jianhua Shen

    Inflammation is thought to play an important role in the pathogenesis of vascular diseases. Lipoprotein‐associated phospholipase A2 (Lp‐PLA2) mediates vascular inflammation through the regulation of lipid metabolism in blood, thus, it has been extensively investigated to identify its role in vascular inflammation‐related diseases, mainly atherosclerosis. Although darapladib, the most advanced Lp‐PLA2 inhibitor, failed to meet the primary endpoints of two large phase III trials in atherosclerosis patients cotreated with standard medical care, the research on Lp‐PLA2 has not been terminated. Novel pathogenic, epidemiologic, genetic, and crystallographic studies regarding Lp‐PLA2 have been reported recently, while novel inhibitors were identified through a fragment‐based lead discovery strategy. More strikingly, recent clinical and preclinical studies revealed that Lp‐PLA2 inhibition showed promising therapeutic effects in diabetic macular edema and Alzheimer's disease. In this review, we not only summarized the knowledge of Lp‐PLA2 established in the past decades but also emphasized new findings in recent years. We hope this review could be valuable for helping researchers acquire a much deeper insight into the nature of Lp‐PLA2, identify more potent and selective Lp‐PLA2 inhibitors, and discover the potential indications of Lp‐PLA2 inhibitors.

  • Recent achievements in developing selective Gq inhibitors
    Med. Res. Rev. (IF 9.791) Pub Date : 2019-06-19
    Hang Zhang; Alexander L. Nielsen; Kristian Strømgaard

    G proteins are key mediators of G protein‐coupled receptor (GPCR) signaling, facilitating a plethora of important physiological processes. The role of G proteins is much less understood than other aspects of GPCR function, which is largely due to the shortage of potent and selective G protein inhibitors. The natural cyclic depsipeptides YM‐254890 and FR900359 are two of the very few known selective inhibitors of the Gq subfamily, and are used as unique pharmacological tools in the study of G q‐mediated signaling. Moreover, a peptide‐based G protein antagonist‐2A (GP‐2A), a 27‐residue peptide (27mer(I860A)) derived from phospholipase C‐β3 (PLC‐β3), and the small molecule BIM‐46187 have also been characterized as selective G q inhibitors within the past 5 years. In this review, we highlight the recent development in chemical syntheses, characterization, and mechanism of action of these selective G q inhibitors. The development and application of G q‐selective inhibitors will expand our knowledge of the structure and function of G protein‐mediated signaling, shed light on the development of inhibitors for other G protein classes, and feed in to drug discovery for diseases where G proteins are implicated, including various forms of cancer.

  • Inducible nitric oxide synthase: Regulation, structure, and inhibition
    Med. Res. Rev. (IF 9.791) Pub Date : 2019-06-13
    Maris A. Cinelli; Ha T. Do; Galen P. Miley; Richard B. Silverman

    A considerable number of human diseases have an inflammatory component, and a key mediator of immune activation and inflammation is inducible nitric oxide synthase (iNOS), which produces nitric oxide (NO) from l‐arginine. Overexpressed or dysregulated iNOS has been implicated in numerous pathologies including sepsis, cancer, neurodegeneration, and various types of pain. Extensive knowledge has been accumulated about the roles iNOS plays in different tissues and organs. Additionally, X‐ray crystal and cryogenic electron microscopy structures have shed new insights on the structure and regulation of this enzyme. Many potent iNOS inhibitors with high selectivity over related NOS isoforms, neuronal NOS, and endothelial NOS, have been discovered, and these drugs have shown promise in animal models of endotoxemia, inflammatory and neuropathic pain, arthritis, and other disorders. A major issue in iNOS inhibitor development is that promising results in animal studies have not translated to humans; there are no iNOS inhibitors approved for human use. In addition to assay limitations, both the dual modalities of iNOS and NO in disease states (ie, protective vs harmful effects) and the different roles and localizations of NOS isoforms create challenges for therapeutic intervention. This review summarizes the structure, function, and regulation of iNOS, with focus on the development of iNOS inhibitors (historical and recent). A better understanding of iNOS’ complex functions is necessary before specific drug candidates can be identified for classical indications such as sepsis, heart failure, and pain; however, newer promising indications for iNOS inhibition, such as depression, neurodegenerative disorders, and epilepsy, have been discovered.

  • Epigenetic polypharmacology: A new frontier for epi‐drug discovery
    Med. Res. Rev. (IF 9.791) Pub Date : 2019-06-20
    Daniela Tomaselli; Alessia Lucidi; Dante Rotili; Antonello Mai

    Recently, despite the great success achieved by the so‐called “magic bullets” in the treatment of different diseases through a marked and specific interaction with the target of interest, the pharmacological research is moving toward the development of “molecular network active compounds,” embracing the related polypharmacology approach. This strategy was born to overcome the main limitations of the single target therapy leading to a superior therapeutic effect, a decrease of adverse reactions, and a reduction of potential mechanism(s) of drug resistance caused by robustness and redundancy of biological pathways. It has become clear that multifactorial diseases such as cancer, neurological, and inflammatory disorders, may require more complex therapeutic approaches hitting a certain biological system as a whole. Concerning epigenetics, the goal of the multi‐epi‐target approach consists in the development of small molecules able to simultaneously and (often) reversibly bind different specific epi‐targets. To date, two dual histone deacetylase/kinase inhibitors (CUDC‐101 and CUDC‐907) are in an advanced stage of clinical trials. In the last years, the growing interest in polypharmacology encouraged the publication of high‐quality reviews on combination therapy and hybrid molecules. Hence, to update the state‐of‐the‐art of these therapeutic approaches avoiding redundancy, herein we focused only on multiple medication therapies and multitargeting compounds exploiting epigenetic plus nonepigenetic drugs reported in the literature in 2018. In addition, all the multi‐epi‐target inhibitors known in literature so far, hitting two or more epigenetic targets, have been included.

  • The role of integrins in the pathogenesis of inflammatory bowel disease: Approved and investigational anti‐integrin therapies
    Med. Res. Rev. (IF 9.791) Pub Date : 2019-06-19
    Iris Dotan; Matthieu Allez; Silvio Danese; Mary Keir; Swati Tole; Jacqueline McBride

    Inflammatory bowel disease (IBD) is characterized by uncontrolled inflammation in the gastrointestinal tract. The underlying pathobiology of IBD includes an increase in infiltrating gut‐homing lymphocytes. Although lymphocyte homing is typically a tightly regulated and stepwise process involving multiple integrins and adhesion molecules expressed on endothelial cells, the distinct roles of integrin‐expressing immune cells is not fully understood in the pathology of IBD. In this review, we detail the involvement of integrins expressed on specific lymphocyte subsets in the pathogenesis of IBD and discuss the current status of approved and investigational integrin‐targeted therapies.

  • An overview of new antitubercular drugs, drug candidates, and their targets
    Med. Res. Rev. (IF 9.791) Pub Date : 2019-06-28
    Aparna Bahuguna; Diwan S. Rawat

    The causative agent of tuberculosis (TB), Mycobacterium tuberculosis and more recently totally drug‐resistant strains of M. tuberculosis, display unique mechanisms to survive in the host. A four‐drug treatment regimen was introduced 40 years ago but the emergence of multidrug‐resistance and more recently TDR necessitates the identification of new targets and drugs for the cure of M. tuberculosis infection. The current efforts in the drug development process are insufficient to completely eradicate the TB epidemic. For almost five decades the TB drug development process remained stagnant. The last 10 years have made sudden progress giving some new and highly promising drugs including bedaquiline, delamanid, and pretomanid. Many of the candidates are repurposed compounds, which were developed to treat other infections but later, exhibited anti‐TB properties also. Each class of drug has a specific target and a definite mode of action. These targets are either involved in cell wall biosynthesis, protein synthesis, DNA/RNA synthesis, or metabolism. This review discusses recent progress in the discovery of newly developed and Food and Drug Administration approved drugs as well as repurposed drugs, their targets, mode of action, drug‐target interactions, and their structure‐activity relationship.

  • Targeting virulence factors as an antimicrobial approach: Pigment inhibitors
    Med. Res. Rev. (IF 9.791) Pub Date : 2019-07-02
    Shuaishuai Ni; Baoli Li; Yixiang Xu; Fei Mao; Xiaokang Li; Lefu Lan; Jin Zhu; Jian Li

    The fascinating and dangerous colored pathogens contain unique chemically pigmented molecules, which give varied and efficient assistance as virulence factors to the crucial reproduction and growth of microbes. Therefore, multiple novel strategies and inhibitors have been developed in recent years that target virulence factor pigments. However, despite the importance and significance of this topic, it has not yet been comprehensively reviewed. Moreover, research groups around the world have made successful progress against antibacterial infections by targeting pigment production, including our serial works on the discovery of CrtN inhibitors against staphyloxanthin production in Staphylococcus aureus. On the basis of the previous achievements and recent progress of our group in this field, this article will be the first comprehensive review of pigment inhibitors against colored pathogens, especially S. aureus infections, and this article includes design strategies, representative case studies, advantages, limitations, and perspectives to guide future research.

  • BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease
    Med. Res. Rev. (IF 9.791) Pub Date : 2019-07-26
    Nour M. Moussa‐Pacha; Shifaa M. Abdin; Hany A. Omar; Hasan Alniss; Taleb H. Al‐Tel

    Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative brain disorder with no current cure. One of the important therapeutic approaches of AD is the inhibition of β‐site APP cleaving enzyme‐1 (BACE1), which is involved in the rate‐limiting step of the cleavage process of the amyloid precursor protein (APP) leading to the generation of the neurotoxic amyloid β (Aβ) protein after the γ‐secretase completes its function. The produced insoluble Aβ aggregates lead to plaques deposition and neurodegeneration. BACE1 is, therefore, one of the attractive targets for the treatment of AD. This approach led to the development of potent BACE1 inhibitors, many of which were advanced to late stages in clinical trials. Nonetheless, the high failure rate of lead drug candidates targeting BACE1 brought to the forefront the need for finding new targets to uncover the mystery behind AD. In this review, we aim to discuss the most promising classes of BACE1 inhibitors with a description and analysis of their pharmacodynamic and pharmacokinetic parameters, with more focus on the lead drug candidates that reached late stages of clinical trials, such as MK8931, AZD‐3293, JNJ‐54861911, E2609, and CNP520. In addition, the manuscript discusses the safety concerns and insignificant physiological effects, which were highlighted for the most successful BACE1 inhibitors. Furthermore, the review demonstrates with increasing evidence that despite tremendous efforts and promising results conceived with BACE1 inhibitors, the latest studies suggest that their clinical use for treating Alzheimer's disease should be reconsidered. Finally, the review sheds light on alternative therapeutic options for targeting AD.

  • Tumor‐derived exosomes (TDEs): How to avoid the sting in the tail
    Med. Res. Rev. (IF 9.791) Pub Date : 2019-07-18
    MeiHua Wan; Bo Ning; Sarah Spiegel; Christopher J. Lyon; Tony Y. Hu

    Exosomes are abundantly secreted extracellular vesicles that accumulate in the circulation and are of great interest for disease diagnosis and evaluation since their contents reflects the phenotype of their cell of origin. Tumor‐derived exosomes (TDEs) are of particular interest for cancer diagnosis and therapy, since most tumor demonstrate highly elevated exosome secretion rates and provide specific information about the genotype of a tumor and its response to treatment. TDEs also contain regulatory factors that can alter the phenotypes of local and distant tissue sites and alter immune cell functions to promote tumor progression. The abundance, information content, regulatory potential, in vivo half‐life, and physical durability of exosomes suggest that TDEs may represent a superior source of diagnostic biomarkers and treatment targets than other materials currently under investigation. This review will summarize current information on mechanisms that may differentially regulate TDE biogenesis, TDE effects on the immune system that promote tumor survival, growth, and metastasis, and new approaches understudy to counteract or utilize TDE properties in cancer therapies.

  • ETS transcription factors as emerging drug targets in cancer
    Med. Res. Rev. (IF 9.791) Pub Date : 2019-03-29
    Michael Hsing; Yuzhuo Wang; Paul S. Rennie; Michael E. Cox; Artem Cherkasov

    The ETS family of proteins consists of 28 transcription factors, many of which have been implicated in development and progression of a variety of cancers. While one family member, ERG, has been rigorously studied in the context of prostate cancer where it plays a critical role, other ETS factors keep emerging as potential hallmark oncodrivers. In recent years, numerous studies have reported initial discoveries of small molecule inhibitors of ETS proteins and opened novel avenues for ETS‐directed cancer therapies. This review summarizes the state of the art data on therapeutic targeting of ETS family members and highlights the corresponding drug discovery strategies.

  • Advance of sporadic Alzheimer's disease animal models
    Med. Res. Rev. (IF 9.791) Pub Date : 2019-07-22
    Lili Zhang; Chen Chen; Marvin SH Mak; Junfeng Lu; Zeqing Wu; Qiuhe Chen; Yifan Han; Yuefeng Li; Rongbiao Pi

    Alzheimer's disease (AD), the most common form of dementia, is a progressive neurodegenerative disease. In the past decades, numbers of promising drug candidates showed significant anti‐AD effects in preclinical studies but failed in clinical trials. One of the major reasons might be the limitation of appropriate animal models for evaluating anti‐AD drugs. More than 95% of AD cases are sporadic AD (sAD). However, the anti‐AD drug candidates were mainly tested in the familial AD (fAD) animal models. The diversity between the sAD and fAD might lead to a high failure rate during the development of anti‐AD drugs. Therefore, an ideal sAD animal model is urgently needed for the development of anti‐AD drugs. Here, we summarized the available sAD animal models, including their methodology, pathologic features, and potential underlying mechanisms. The limitations of these sAD animal models and future trends in the field were also discussed.

  • Phage therapy: Current status and perspectives
    Med. Res. Rev. (IF 9.791) Pub Date : 2019-05-07
    Andrzej Górski; Ryszard Międzybrodzki; Grzegorz Węgrzyn; Ewa Jończyk‐Matysiak; Jan Borysowski; Beata Weber‐Dąbrowska

    The spread of antimicrobial resistant bacterial pathogens combined with the lack of new drug classes in the antibiotic pipeline causes a resurgence of the use of bacterial viruses (phages) to treat bacterial infections (phage therapy [PT]). There has been a substantial increase in patients subjected to this experimental therapy and emergence of new PT centers in Europe and the United States paralleled by one clinical trial completed in accord with good medical practice (GMP) requirements and a few others underway. What is more, evidence has been accumulating to suggest that phages can also exert anti‐inflammatory and immunomodulatory action which opens new pathways for the development of novel targets for PT. Here we present the status quo of the PT, recent regulatory, and clinical developments as well as new perspectives for its wider application in clinical medicine.

  • Carbon monoxide: An emerging therapy for acute kidney injury
    Med. Res. Rev. (IF 9.791) Pub Date : 2019-12-09
    Xiaoxiao Yang, Mark de Caestecker, Leo E. Otterbein, Binghe Wang

    Treating acute kidney injury (AKI) represents an important unmet medical need both in terms of the seriousness of this medical problem and the number of patients. There is also a large untapped market opportunity in treating AKI. Over the years, there has been much effort in search of therapeutics with minimal success. However, over the same time period, new understanding of the underlying pathobiology and molecular mechanisms of kidney injury have undoubtedly helped the search for new therapeutics. Along this line, carbon monoxide (CO) has emerged as a promising therapeutic agent because of its demonstrated cytoprotective, and immunomodulatory effects. CO has also been shown to sensitize cancer, but not normal cells, to chemotherapy. This is particularly important in treating cisplatin‐induced AKI, a common clinical problem that develops in patients receiving cisplatin therapies for a number of different solid organ malignancies. This review will examine and make the case that CO be developed into a therapeutic agent against AKI.

  • Overcoming the delivery barrier of oligonucleotide drugs and enhancing nucleoside drug efficiency: The use of nucleolipids
    Med. Res. Rev. (IF 9.791) Pub Date : 2019-12-09
    Xinyang Zhou, Shuhe Wang, Yuejie Zhu, Yufei Pan, Lihe Zhang, Zhenjun Yang

    With the rapid development of synthetic technology and biological technology, many nucleic acid‐based drugs have entered the clinical trials. However, their inherent disabilities in actively and efficiently penetrating cell membranes still severely restrict their further application. The main drawback of cationic lipids, which have been widely used as nonviral vectors of nucleic acids, is their high cytotoxicity. A series of nucleoside‐based or nucleotide‐based nucleolipids have been reported in recent years, due to their oligonucleotide delivery capacity and low toxicity in comparison with cationic lipids. Lipophilic prodrugs of nucleoside analogs have extremely similar structures with nucleolipid vectors and are thus helpful for improving the transmembrane ability. This review introduces the progress of nucleolipids and provides new strategies for improving the delivery efficiency of nucleic acid‐based drugs, as well as lipophilic prodrugs of nucleosides or nucleotides for antiviral or anticancer therapies.

  • Expert insights: The potential role of the gut microbiome‐bile acid‐brain axis in the development and progression of Alzheimer's disease and hepatic encephalopathy
    Med. Res. Rev. (IF 9.791) Pub Date : 2019-12-05
    Wei Jia, Cynthia Rajani, Rima Kaddurah‐Daouk, Houkai Li

    Recent epidemiological and molecular studies have linked the disruption of cholesterol homeostasis to increased risk for developing Alzheimer's disease (AD). Emerging evidence also suggests that brain cholesterol accumulation contributes to the progression of hepatic encephalopathy (HE) via bile acid (BA)‐mediated effects on the farnesoid X receptor. In this perspective paper, we reviewed several recently published studies that suggested a role for the gut microbiota transformation of BAs as a factor in AD and HE development/progression. We hypothesize that in addition to cholesterol elimination pathways, alteration of the gut microbiota and subsequent changes in both the serum and brain BA profiles are mechanistically involved in the development of both AD and HE, and thus, are a potential target for the prevention and treatment of the two diseases. Our understanding of the microbiome‐BAs‐brain axis in central nervous system disease is still evolving, and critical questions regarding the emerging links among central, peripheral, and intestinal metabolic failures contributing to brain health and disease during aging have yet to be addressed.

  • Synthesis of histidine kinase inhibitors and their biological properties
    Med. Res. Rev. (IF 9.791) Pub Date : 2019-12-05
    Miyanou Rosales‐Hurtado, Patrick Meffre, Hendrik Szurmant, Zohra Benfodda

    Infections caused by multidrug‐resistant bacteria represent a significant and ever‐increasing cause of morbidity and mortality. There is thus an urgent need to develop efficient and well‐tolerated antibacterials targeting unique cellular processes. Numerous studies have led to the identification of new biological targets to fight bacterial resistance. Two‐component signal transduction systems are widely employed by bacteria to translate external and cellular signals into a cellular response. They are ubiquitous in bacteria, absent in the animal kingdom and are integrated into various virulence pathways. Several chemical series, including isothiazolidones, imidazolium salts, benzoxazines, salicylanilides, thiophenes, thiazolidiones, benzimidazoles, and other derivatives deduced by different approaches have been reported in the literature to have histidine kinase (HK) inhibitory activity. In this review, we report on the design and the synthesis of these HKs inhibitors and their potential to serve as antibacterial agents.

  • Agonists and inhibitors of the STING pathway: Potential agents for immunotherapy
    Med. Res. Rev. (IF 9.791) Pub Date : 2019-12-02
    Jun‐Jun Wu, Lang Zhao, Hong‐Guo Hu, Wen‐Hao Li, Yan‐Mei Li

    Since being discovered in 2008, the STING (stimulator of interferon genes) pathway has gradually been recognized as a central and promising target for immunotherapy. The STING pathway can be stimulated by cyclic dinucleotides (CDNs), leading to the type I interferons (IFN) production for immunotherapy for cancer or other diseases. However, the negative charges, hydrophilicity, and instability of CDNs have hindered their further applications. In addition, chronic activation of the STING pathway has been found to be involved in autoimmune diseases as IFN overproduction. Thus, research and development of STING agonists and inhibitors has been a hot field for the treatment of several diseases. The past several years, especially 2018, has seen increasingly rapid advances in this field. Here, this review summarizes the synthesis and modification of CDNs, the identification of nonnucleotide agonists, the recent progress in delivery systems and the medical applications, such as personalized vaccine adjuvants, in detail. In addition, in this review, we summarize the STING inhibitors’ advances from two aspects, covalent, and noncovalent inhibitors.

  • Strategies for developing pregnane X receptor antagonists: Implications from metabolism to cancer
    Med. Res. Rev. (IF 9.791) Pub Date : 2019-11-28
    Sergio C. Chai, William C. Wright, Taosheng Chen

    Pregnane X receptor (PXR) is a ligand‐activated nuclear receptor (NR) that was originally identified as a master regulator of xenobiotic detoxification. It regulates the expression of drug‐metabolizing enzymes and transporters to control the degradation and excretion of endobiotics and xenobiotics, including therapeutic agents. The metabolism and disposition of drugs might compromise their efficacy and possibly cause drug toxicity and/or drug resistance. Because many drugs can promiscuously bind and activate PXR, PXR antagonists might have therapeutic value in preventing and overcoming drug‐induced PXR‐mediated drug toxicity and drug resistance. Furthermore, PXR is now known to have broader cellular functions, including the regulation of cell proliferation, and glucose and lipid metabolism. Thus, PXR might be involved in human diseases such as cancer and metabolic diseases. The importance of PXR antagonists is discussed in the context of the role of PXR in xenobiotic sensing and other disease‐related pathways. This review focuses on the development of PXR antagonists, which has been hampered by the promiscuity of PXR ligand binding. However, substantial progress has been made in recent years, suggesting that it is feasible to develop selective PXR antagonists. We discuss the current status, challenges, and strategies in developing selective PXR antagonists. The strategies are based on the molecular mechanisms of antagonism in related NRs that can be applied to the design of PXR antagonists, primarily driven by structural information.

  • Demolishing the great wall of biofilms in Gram‐negative bacteria: To disrupt or disperse?
    Med. Res. Rev. (IF 9.791) Pub Date : 2019-11-20
    Miao Yu, Song Lin Chua

    Bacterial infections lead to high morbidity and mortality globally. While current therapies against bacteria often employ antibiotics, most bacterial pathogens can form biofilms and prevent effective treatment of infections. Biofilm cells can aggregate and encased themselves in a self‐secreted protective exopolymeric matrix, to reduce the penetration by antibiotics. Biofilm formation is mediated by c‐di‐GMP signaling, the ubiquitous secondary messenger in bacteria. Synthesis of c‐di‐GMP by diguanylate cyclases leads to biofilm formation via the loss of motility, increased surface attachment, and production of biofilm matrix, whereas c‐di‐GMP degradation by phosphodiesterases causes biofilm dispersal to new sites via increased bacterial motility and matrix breakdown. The highly variable nature of biofilm development and antimicrobial tolerance imposes tremendous challenges in conventional antimicrobial therapies, indicating an imperative need to develop anti‐biofilm drugs against biofilm infections. In this review, we focus on two main emergent approaches—active dispersal and disruption. While both approaches aim to demolish biofilms, we will discuss their fundamental differences and associated methods. Active dispersal of biofilms involves signaling the bacterial cells to leave the biofilm, where resident cells ditch their sessile lifestyle, gain motility and self‐degrade their matrix. Biofilm disruption leads to direct matrix degradation that forcibly releases embedded biofilm cells. Without the protection of biofilm matrix, released bacterial cells are highly exposed to antimicrobials, leading to their eradication in biofilm infections. Understanding the advantages and disadvantages of both approaches will allow optimized utility with antimicrobials in clinical settings.

  • Autophagy modulators for the treatment of oral and esophageal squamous cell carcinomas
    Med. Res. Rev. (IF 9.791) Pub Date : 2019-11-19
    Tuhina Khan, Nicola Relitti, Margherita Brindisi, Stefania Magnano, Daniela Zisterer, Sandra Gemma, Stefania Butini, Giuseppe Campiani

    Oral squamous cell carcinomas (OSCC) and esophageal squamous cell carcinomas (ESCC) exhibit a survival rate of less than 60% and 40%, respectively. Late‐stage diagnosis and lack of effective treatment strategies make both OSCC and ESCC a significant health burden. Autophagy, a lysosome‐dependent catabolic process, involves the degradation of intracellular components to maintain cell homeostasis. Targeting autophagy has been highlighted as a feasible therapeutic strategy with clinical utility in cancer treatment, although its associated regulatory mechanisms remain elusive. The detection of relevant biomarkers in biological fluids has been anticipated to facilitate early diagnosis and/or prognosis for these tumors. In this context, recent studies have indicated the presence of specific proteins and small RNAs, detectable in circulating plasma and serum, as biomarkers. Interestingly, the interplay between biomarkers (eg, exosomal microRNAs) and autophagic processes could be exploited in the quest for targeted and more effective therapies for OSCC and ESCC. In this review, we give an overview of the available biomarkers and innovative targeted therapeutic strategies, including the application of autophagy modulators in OSCC and ESCC. Additionally, we provide a viewpoint on the state of the art and on future therapeutic perspectives combining the early detection of relevant biomarkers with drug discovery for the treatment of OSCC and ESCC.

  • Design and synthesis of glycomimetics: Recent advances
    Med. Res. Rev. (IF 9.791) Pub Date : 2019-07-30
    Alice Tamburrini, Cinzia Colombo, Anna Bernardi

    In the past few decades, our understanding of glycan information‐encoding power has notably increased, thus leading to a significant growth also in the design and synthesis of glycomimetic probes. Combining data from multiple analytical sources, such as crystallography, nuclear magnetic resonance spectroscopy, and other biophysical methods (eg, surface plasmon resonance and carbohydrate microarrays) has allowed to shed light on the key interaction events between carbohydrates and their protein‐targets. However, the low metabolic stability of carbohydrates and their high hydrophilicity, which translates in low bioavailability, undermine their development as drugs. In this framework, the design of chemically modified analogues (called carbohydrate mimics or glycomimetics) appears as a valid alternative for the development of therapeutic agents. Glycomimetics, as structural and functional mimics of carbohydrates, can replace the native ligands in the interaction with target proteins, but are designed to show enhanced enzymatic stability and bioavailability and, possibly, an improved affinity and selectivity toward the target. In the present account, we specifically focus on the most recent advances in the design and synthesis of glycomimetics. In particular, we highlight the efforts of the scientific community in the development of straightforward synthetic procedures for the preparation of sugar mimics and in their preliminary biological evaluation.

  • Therapeutic strategies for targeting telomerase in cancer
    Med. Res. Rev. (IF 9.791) Pub Date : 2019-07-30
    Xing Chen, Wen‐Jian Tang, Jing Bo Shi, Ming Ming Liu, Xin‐Hua Liu

    Telomere and telomerase play important roles in abnormal cell proliferation, metastasis, stem cell maintenance, and immortalization in various cancers. Therefore, designing of drugs targeting telomerase and telomere is of great significance. Over the past two decades, considerable knowledge regarding telomere and telomerase has been accumulated, which provides theoretical support for the design of therapeutic strategies such as telomere elongation. Therefore, the development of telomere‐based therapies such as nucleoside analogs, non‐nucleoside small molecules, antisense technology, ribozymes, and dominant negative human telomerase reverse transcriptase are being prioritized for eradicating a majority of tumors. While the benefits of telomere‐based therapies are obvious, there is a need to address the limitations of various therapeutic strategies to improve the possibility of clinical applications. In this study, current knowledge of telomere and telomerase is discussed, and therapeutic strategies based on recent research are reviewed.

  • Protein‐protein interactions as antibiotic targets: A medicinal chemistry perspective
    Med. Res. Rev. (IF 9.791) Pub Date : 2018-07-13
    Peter J. Cossar, Peter J. Lewis, Adam McCluskey

    There are 27 small molecule protein‐protein interaction (PPI) modulators in Phase I, II, and III clinical trials targeting cancer, viruses, autoimmune disorders, and as immune suppression agents. Targeting PPIs as an antibiotic drug discovery strategy remains in relative infancy by comparison. However, a number of molecules are in development which target PPI within the replisome, divisome, transcriptome, and translatome are showing significant promise at the medicinal chemistry stage of drug development. Hence, the success of future PPI agents as antibiotics will build upon the techniques and design strategies of these molecules.

  • The aryl hydrocarbon receptor (AhR) as a breast cancer drug target
    Med. Res. Rev. (IF 9.791) Pub Date : 2019-11-12
    Jennifer R. Baker, Jennette A. Sakoff, Adam McCluskey

    Breast cancer is the most common cancer in women, with more than 1.7 million diagnoses worldwide per annum. Metastatic breast cancer remains incurable, and the presence of triple‐negative phenotypes makes targeted treatment impossible. The aryl hydrocarbon receptor (AhR), most commonly associated with the metabolism of xenobiotic ligands, has emerged as a promising biological target for the treatment of this deadly disease. Ligands for the AhR can be classed as exogenous or endogenous and may have agonistic or antagonistic activity. It has been well reported that agonistic ligands may have potent and selective growth inhibition activity in a number of oncogenic cell lines, and one (aminoflavone) has progressed to phase I clinical trials for breast cancer sufferers. In this study, we examine the current state of the literature in this area and elucidate the promising advances that are being made in hijacking the cytosolic‐to‐nuclear pathway of the AhR for the possible future treatment of breast cancer.

  • Modulating the tumor microenvironment with new therapeutic nanoparticles: A promising paradigm for tumor treatment
    Med. Res. Rev. (IF 9.791) Pub Date : 2019-11-11
    Yinlong Zhang, Shih‐Hsin Ho, Bozhao Li, Guangjun Nie, Suping Li

    To better make nanomedicine entering the clinic, developing new rationally designed nanotherapeutics with a deeper understanding of tumor biology is required. The tumor microenvironment is similar to the inflammatory response in a healing wound, the milieu of which promotes tumor cell invasion and metastasis. Successful targeting of the microenvironmental components with effective nanotherapeutics to modulate the tumor microvessels or restore the homeostatic mechanisms in the tumor stroma will offer new hope for cancer treatment. We here highlight the progress in constructing nanotherapeutics to target or modulate the tumor microenvironment. We discuss the factors necessary for nanomedicines to become a new paradigm in cancer therapy, including the selection of drugs and therapeutic targets, controllable synthesis, and tempo‐spatial drug release.

  • Hybrid molecules with potential in vitro antiplasmodial and in vivo antimalarial activity against drug‐resistant Plasmodium falciparum
    Med. Res. Rev. (IF 9.791) Pub Date : 2019-11-06
    Lian‐Shun Feng, Zhi Xu, Le Chang, Chuan Li, Xiao‐Fei Yan, Chuan Gao, Chao Ding, Feng Zhao, Feng Shi, Xiang Wu

    Malaria is a tropical disease, leading to around half a million deaths annually. Antimalarials such as quinolines are crucial to fight against malaria, but malaria control is extremely challenged by the limited pipeline of effective pharmaceuticals against drug‐resistant strains of Plasmodium falciparum which are resistant toward almost all currently accessible antimalarials. To tackle the growing resistance, new antimalarial drugs are needed urgently. Hybrid molecules which contain two or more pharmacophores have the potential to overcome the drug resistance, and hybridization of quinoline privileged antimalarial building block with other antimalarial pharmacophores may provide novel molecules with enhanced in vitro and in vivo activity against drug‐resistant (including multidrug‐resistant) P falciparum. In recent years, numerous of quinoline hybrids were developed, and their activities against a panel of drug‐resistant P falciparum strains were screened. Some of quinoline hybrids were found to possess promising in vitro and in vivo potency. This review emphasized quinoline hybrid molecules with potential in vitro antiplasmodial and in vivo antimalarial activity against drug‐resistant P falciparum, covering articles published between 2010 and 2019.

  • Inhibitors of microsomal prostaglandin E2 synthase-1 enzyme as emerging anti-inflammatory candidates.
    Med. Res. Rev. (IF 9.791) Pub Date : 2014-07-16
    Malkeet Singh Bahia,Yogesh Kumar Katare,Om Silakari,Bhawna Vyas,Pragati Silakari

    Cyclooxygenases (COX-1 and COX-2) catalyze the conversion of arachidonic acid (AA) into PGH2 that is further metabolized by terminal prostaglandin (PG) synthases into biologically active PGs, for example, prostaglandin E2 (PGE2), prostacyclin I2 (PGI2), thromboxane A2 (TXA2), prostaglandin D2 (PGD2), and prostaglandin F2 alpha (PGF2α). Among them, PGE2 is a widely distributed PG in the human body, and an important mediator of inflammatory processes. The successful modulation of this PG provides a beneficial strategy for the potential anti-inflammatory therapy. For instance, nonsteroidal anti-inflammatory agents (NSAIDs), both classical nonselective (cNSAIDs) and the selective COX-2 inhibitors (coxibs) attenuate the generation of PGH2 from AA that in turn reduces the synthesis of PGE2 and modifies the inflammatory conditions. However, the long-term use of these agents causes severe side effects due to the nonselective inhibition of other PGs, such as PGI2 and TXA2, etc. Microsomal prostaglandin E2 synthase-1 (mPGES-1), a downstream PG synthase, specifically catalyzes the biosynthesis of COX-2-derived PGE2 from PGH2, and describes itself as a valuable therapeutic target for the treatment of acute and chronic inflammatory disease conditions. Therefore, the small molecule inhibitors of mPGES-1 would serve as a beneficial anti-inflammatory therapy, with reduced side effects that are usually associated with the nonselective inhibition of PG biosynthesis.

  • Bioactive taxoids from the Japanese yew Taxus cuspidata.
    Med. Res. Rev. (IF 9.791) Pub Date : 2002-04-05
    Jun'ichi Kobayashi,Hideyuki Shigemori

    A series of new taxoids, named taxuspines A-H and J-Z (1-25) and taxezopidines A-H and J-L (26-36), have been isolated together with 37 known taxoids (37-73) including paclitaxel (53) from the Japanese yew, Taxus cuspidata Sieb. et Zucc. (Taxaceae). These new taxoids possess various skeletons containing 5/7/6, 6/10/6, 6/5/5/6, 6/8/6, or 6/12-membered ring systems. Among the new taxoids, some non-taxol-type compounds remarkably reduced CaCl(2)-induced depolymerization of microtubules, or increased cellular accumulation of vincristine in multidrug-resistant tumor cells as potent as verapamil. On the other hand, chemical derivatization of taxinine (37), one of major taxoids obtained from this yew, led to the discovery of unusual reactions of taxinine derivatives. Here we describe our recent results on the isolation, structure elucidation, and bioactivity of these new and known taxoids and the formation of unexpected products of the unusual reactions of taxinine.

  • Nonsteroidal aromatase inhibitors: recent advances.
    Med. Res. Rev. (IF 9.791) Pub Date : 2002-04-05
    Maurizio Recanatini,Andrea Cavalli,Piero Valenti

    Aromatase is the cytochrome P450 enzyme responsible for the last step of estrogen biosynthesis, and aromatase inhibitors constitute an important class of drugs in clinical use for the treatment of breast cancer. Nonsteroidal aromatase inhibitors (NSAIs) are competitive inhibitors of aromatase, which bind to the enzyme active site by coordinating the iron atom present in the heme group of the P450 protein. Presently, third generation NSAIs are in use, and research efforts are being carried out both to identify new molecules of therapeutic interest and to clarify the mechanism of action. In this article, we present a survey of the compounds that have been recently reported as NSAIs, to provide a broad view on the general structure-activity relationships of the class. Moreover, starting from the current knowledge of the mechanistic aspects of aromatase action and from recent theoretical work on the molecular modeling of both enzyme and inhibitors, we try to indicate a way to integrate these different studies in view of a more general understanding of the aromeatase-inhibitor system. Finally, some aspects regarding the possible future development of the field are considered briefly.

  • Chemical control of phospholipid distribution across bilayer membranes.
    Med. Res. Rev. (IF 9.791) Pub Date : 2002-04-05
    J Middleton Boon,Bradley D Smith

    Most biological membranes possess an asymmetric transbilayer distribution of phospholipids. Endogenous enzymes expend energy to maintain the arrangement by promoting the rate of phospholipid translocation, or flip-flop. Researchers have discovered ways to modify this distribution through the use of chemicals. This review presents a critical analysis of the phospholipid asymmetry data in the literature followed by a brief overview of the maintenance and physiological consequences of phospholipid asymmetry, and finishes with a list of chemical ways to alter phospholipid distribution by enhancement of flip-flop.

  • Transferrin/transferrin receptor-mediated drug delivery.
    Med. Res. Rev. (IF 9.791) Pub Date : 2002-04-05
    Hongyan Li,Zhong Ming Qian

    Since transferrin was discovered more than half a century ago, a considerable effort has been made towards understanding tranferrin-mediated iron uptake. However, it was not until recently with the identification and characterization of several new genes related to iron homeostasis, such as the hemochromatosis protein HFE and the iron transporter DMT1, that our knowledge has been advanced dramatically. A major pathway for cellular iron uptake is through internalization of the complex of iron-bound transferrin and the transferrin receptor, which is negatively modulated by HFE, a protein related to hereditary hemochromatosis. Iron is released from transferrin as the result of the acidic pH in endosome and then is transported to the cytosol by DMT1. The iron is then utilized as a cofactor by heme and ribonucleotide reductase or stored in ferritin. Apart from iron, many other metal ions of therapeutic and diagnostic interests can also bind to transferrin at the iron sites and their transferrin complexes can be recognized by many cells. Therefore, transferrin has been thought as a "delivery system" for many beneficial and harmful metal ions into the cells. Transferrin has also be widely applied as a targeting ligand in the active targeting of anticancer agents, proteins, and genes to primary proliferating malignant cells that overexpress transferrin receptors. This is achieved by conjugation of transferrin with drugs, proteins, hybride systems with marcomolecules and as liposomal-coated systems. Conjugates of anticancer drugs with transferrin can significantly improve the selectivity and toxicity and overcome drug resistance, thereby leading to a better treatment. The coupling of DNA to transferrin via a polycation such as polylysine or via cationic liposomes can target and transfer of the extrogenous DNA particularly into proliferating cells through receptor-mediated endocytosis. These kinds of non-viral vectors are potential alternatives to viral vectors for gene therapy, if the transfection efficiency can be improved. Moreover, transferrin receptors have shown potentials in delivery of therapeutic drugs or genes into the brain across blood-brain barrier.

  • Therapeutic ultrasound: its application in drug delivery.
    Med. Res. Rev. (IF 9.791) Pub Date : 2002-02-22
    Ka-yun Ng,Yang Liu

    Ultrasound is best known for its imaging capability in diagnostic medicine. However, there have been considerable efforts recently to develop therapeutic uses for it. The purpose of this review is to summarize some of the recent advances made in the area of therapeutic ultrasound as they relate to drug delivery. In particular, this review will focus on the applications of ultrasound to enhance the delivery and effect of three distinctive therapeutic drug classes: chemotherapeutic, thrombolytic, and gene-based drugs. In addition, ultrasound contrast agents have been recently developed for diagnostic ultrasound. New experimental evidence suggests that these contrast agents can be used as exogenous cavitation nuclei for enhancement of drug and gene delivery. Thus, brief review of this new class of agents and their roles in drug delivery will also be provided. By comparison to diagnostic ultrasound, progress in therapeutic use of ultrasound has been somewhat limited. The recent successes in ultrasound-related drug delivery research positions ultrasound as therapeutic tool for drug delivery in the future.

  • Binding interactions between peptides and proteins of the class II major histocompatibility complex.
    Med. Res. Rev. (IF 9.791) Pub Date : 2002-02-22
    Benjamin J McFarland,Craig Beeson

    The activation of helper T cells by peptides bound to proteins of the class II Major Histocompatibility Complex (MHC II) is pivotal to the initiation of an immune response. The primary functional requirement imposed on MHC II proteins is the ability to efficiently bind thousands of different peptides. Structurally, this is reflected in a unique architecture of binding interactions. The peptide is bound in an extended conformation within a groove on the membrane distal surface of the protein that is lined with several pockets that can accommodate peptide side-chains. Conserved MHC II protein residues also form hydrogen bonds along the length of the peptide main-chain. Here we review recent advances in the study of peptide-MHC II protein reactions that have led to an enhanced understanding of binding energetics. These results demonstrate that peptide-MHC II protein complexes achieve high affinity binding from the array of hydrogen bonds that are energetically segregated from the pocket interactions, which can then add to an intrinsic hydrogen bond-mediated affinity. Thus, MHC II proteins are unlike antibodies, which utilize cooperativity among binding interactions to achieve high affinity and specificity. The significance of these observations is discussed within the context of possible mechanisms for the HLA-DM protein that regulates peptide presentation in vivo and the design of non-peptide molecules that can bind MHC II proteins and act as vaccines or immune modulators.

  • Inhibition of LFA-1/ICAM-1 and VLA-4/VCAM-1 as a therapeutic approach to inflammation and autoimmune diseases.
    Med. Res. Rev. (IF 9.791) Pub Date : 2002-02-22
    Helena Yusuf-Makagiansar,Meagan E Anderson,Tatyana V Yakovleva,Joseph S Murray,Teruna J Siahaan

    This review focuses on providing insights into the structural basis and clinical relevance of LFA-1 and VLA-4 inhibition by peptides and small molecules as adhesion-based therapeutic strategies for inflammation and autoimmune diseases. Interactions of cell adhesion molecules (CAM) play central roles in mediating immune and inflammatory responses. Leukocyte function-associated antigen (LFA-1, alpha(L)beta(2), and CD11a/CD18) and very late antigen (VLA-4, alpha(4)beta(1), and CD49d/CD29) are members of integrin-type CAM that are predominantly involved in leukocyte trafficking and extravasation. LFA-1 is exclusively expressed on leukocytes and interacts with its ligands ICAM-1, -2, and -3 to promote a variety of homotypic and heterotypic cell adhesion events required for normal and pathologic functions of the immune systems. VLA-4 is expressed mainly on lymphocyte, monocytes, and eosinophils, but is not found on neutrophils. VLA-4 interacts with its ligands VCAM-1 and fibronectin (FN) CS1 during chronic inflammatory diseases, such as rheumatoid arthritis, asthma, psoriasis, transplant-rejection, and allergy. Blockade of LFA-1 and VLA-4 interactions with their ligands is a potential target for immunosuppression. LFA-1 and VLA-4 antagonists (antibodies, peptides, and small molecules) are being developed for controlling inflammation and autoimmune diseases. The therapeutic intervention of mostly mAb-based has been extensively studied. However, due to the challenging relative efficacy/safety ratio of mAb-based therapy application, especially in terms of systemic administration and immunogenic potential, strategic alternatives in the forms of peptide, peptide mimetic inhibitors, and small molecule non-peptide antagonists are being sought. Linear and cyclic peptides derived from the sequences of LFA-1, ICAM-1, ICAM-2, VCAM-1, and FN C1 have been shown to have inhibitory effects in vitro and in vivo. Finally, understanding the mechanism of LFA-1 and VLA-4 binding to their ligands has become a fundamental basis in developing therapeutic agents for inflammation and autoimmune diseases.

  • Natural products as probes of cell biology: 20 years of didemnin research.
    Med. Res. Rev. (IF 9.791) Pub Date : 2002-02-22
    Matthew D Vera,Madeleine M Joullié

    The discovery of the didemnin family of marine depsipeptides launched an exciting and intriguing chapter in natural product chemistry. The unusual structure of the didemnin congeners has led to several total syntheses by research groups from around the world. The impressive in vitro and in vivo biological activities of the didemnins resulted in the first human clinical trials in the U.S. of a marine natural product against cancer, and additional clinical trials of a second-generation didemnin, dehydrodidemnin B (aplidine), are underway. As we mark the 20-year anniversary of the discovery of the didemnins, this class of natural products continues to stimulate active research in fields ranging from synthetic and medicinal chemistry to clinical oncology and cell biology. While some progress was made in dissecting the molecular mechanism of action and in establishing structure-activity relationships, there are still more questions than answers. This review covers the recent didemnin literature, highlighting the work directed towards understanding how this group of natural products interact with fundamental processes such as cell proliferation, protein biosynthesis, and apoptosis. The didemnin field illustrates how natural product chemistry may be used as a critical tool for the study of cell biology.

  • The cryptophycins: their synthesis and anticancer activity.
    Med. Res. Rev. (IF 9.791) Pub Date : 2002-02-22
    MariJean Eggen,Gunda I Georg

    The cryptophycins are a unique family of 16-membered macrolide antimitotic agents isolated from the cyanobacteria Nostoc sp. Their molecular target is tubulin protein wherein they are the most potent known stabilizers of microtubule dynamics and depolymerize microtubules at higher concentrations. They also deactivate the Bcl2 protein and produce apoptotic response much more quickly and at considerably lower concentrations than clinically utilized compounds. The presence of several amide and ester linkages within the cryptophycin core provides access to very convergent total synthetic approaches. Likewise, the modularity of the structure renders their synthesis amenable to structure-activity studies in several regions of the molecule. The in vivo hydrolytic instability of the C5 ester was a key obstacle to the successful identification of a clinical candidate. This problem was ameliorated by increased substitution at C6 as in the presence of gem-dimethyl substitution in the clinical candidate, cryptophycin-52.

  • Statins and progressive renal disease.
    Med. Res. Rev. (IF 9.791) Pub Date : 2001-12-18
    Michele Buemi,Massimino Senatore,Francesco Corica,Carmela Aloisi,Adolfo Romeo,Emanuela Cavallaro,Fulvio Floccari,Domenico Tramontana,Nicola Frisina

    Thanks to the administration of hypocholesterolemic drugs, important advances have been made in the treatment of patients with progressive renal disease. In vitro and in vivo findings demonstrate that statins, the inhibitors of HMG-CoA reductase, can provide protection against kidney diseases characterized by inflammation and/or enhanced proliferation of epithelial cells occurring in rapidly progressive glomerulonephritis, or by increased proliferation of mesangial cells occurring in IgA nephropathy. Many of the beneficial effects obtained occur independent of reduced cholesterol levels because statins can directly inhibit the proliferation of different cell types (e.g., mesangial, renal tubular, and vascular smooth muscle cells), and can also modulate the inflammatory response, thus inhibiting macrophage recruitment and activation, as well as fibrosis. The mechanisms underlying the action of statins are not yet well understood, although recent data in the literature indicate that they can directly affect the proliferation/apoptosis balance, the down-regulation of inflammatory chemokines, and the cytogenic messages mediated by the GTPases Ras superfamily. Therefore, as well as reducing serum lipids, statins and other lipid-lowering agents may directly influence intracellular signaling pathways involved in the prenylation of low molecular weight proteins that play a crucial role in cell signal transduction and cell activation. Statins appear to have important potential in the treatment of progressive renal disease, although further studies are required to confirm this in humans.

  • Antioxidant and other biological activities of phenols from olives and olive oil.
    Med. Res. Rev. (IF 9.791) Pub Date : 2001-12-18
    Francesco Visioli,Andrea Poli,Claudio Gall

    Olive oil is the principal source of fats in the Mediterranean diet, which has been associated with a lower incidence of coronary heart disease and certain cancers. Phenolic compounds, e.g., hydroxytyrosol and oleuropein, in extra-virgin olive oil are responsible for its peculiar pungent taste and for its high stability. Recent findings demonstrate that olive oil phenolics are powerful antioxidants, both in vitro and in vivo, and possess other potent biological activities that could partially account for the observed healthful effects of the Mediterranean diet.

  • Design of clinically useful iron(III)-selective chelators.
    Med. Res. Rev. (IF 9.791) Pub Date : 2001-12-18
    Zu D Liu,Robert C Hider

    Iron overload is a serious clinical condition which can be largely prevented by the use of iron-specific chelating agents. Desferrioxamine-B, the most widely used iron chelator in haematology over the past 30 years, has a major disadvantage of being orally inactive. Consequently, the successful design of an orally active, nontoxic, selective iron chelator has become a much sought after goal. In order to identify an ideal iron chelator for clinical use, a range of specifications must be considered such as metal selectivity and affinity, kinetic stability of the complex, bioavailability and toxicity. A wide range of chelator types bind iron(III) and of these, hexa-, tri-, and bidentate are capable of providing iron(III) with the favoured octahedral environment. In this review, the comparative properties of such ligands are discussed, examples being selected from hydroxamates, aminocarboxylates, hydroxypyridinones, orthosubstituted phenols and triazoles.

  • Cell surface heparan sulfate and its roles in assisting viral infections.
    Med. Res. Rev. (IF 9.791) Pub Date : 2001-12-18
    Jian Liu,Suzanne C Thorp

    Heparan sulfate, a highly sulfated polysaccharide, is present on the surface of mammalian cells and in the extracellular matrix in large quantities. The sulfated monosaccharide sequences within heparan sulfate determine the protein binding specificity and regulate biological functions. Numerous viruses and parasites utilize cell surface heparan sulfate as receptors to infect target cells. Due to the structural complexity of heparan sulfate, it was considered a nonspecific cell surface receptor by interacting with the positive motifs of viral proteins. However, recent studies reveal that heparan sulfate plays multiple roles in assisting viral infection, and the activities in promoting viral infections require unique monosaccharide sequences, suggesting that heparan sulfate could serve as a specific receptor for viral infection. The currently available techniques for the structural analysis of heparan sulfate provide essential information about the specific roles of heparan sulfate in assisting viral infections. The knowledge accumulated in this fast growing field will permit us to have a better understanding of the mechanism of viral infection and will lead to the development of new antiviral agents.

  • Peroxisome proliferator-activated receptor (PPAR) modulators: diabetes and beyond.
    Med. Res. Rev. (IF 9.791) Pub Date : 2001-10-19
    A B Jones

    Peroxisome proliferator-activated receptors (PPARs) are a class of ligand modulated transcription factors with a prominent role in the regulation of metabolic processes. This report is intended to provide a limited introduction to the PPAR field, sketched with reference to one early series of PPAR ligands.

  • Different ligands-different receptor conformations: modeling of the hER alpha LBD in complex with agonists and antagonists.
    Med. Res. Rev. (IF 9.791) Pub Date : 2001-10-19
    U Egner,N Heinrich,M Ruff,M Gangloff,A Mueller-Fahrnow,J M Wurtz

    The aim of this study is to compare crystal structures of nuclear receptor ligand binding domains in complex with different agonists and partial agonists to achieve a better understanding of the three-dimensional structures and their ligand-induced conformational changes. This led to the identification of structurally conserved "rigid" regions and more flexible parts of the proteins. The analysis was found to be of great value in fitting selected non-steroidal compounds into the human estrogen receptor alpha (hER alpha) ligand binding pocket. The experimentally determined binding affinities for a number of 2-aryl indoles and 2-aryl indenones are in good agreement with the subsequently modeled binding interactions. To date, no crystal structure is published for a complex with a pure antagonist. We therefore used the available structural information on complexes with partial agonists and the crystal structure of a mutant protein in complex with estradiol displaying a similar conformation to predict binding interactions for antagonists. The results are discussed in detail.

  • Chemical genomics: functional analysis of orphan nuclear receptors in the regulation of bile acid metabolism.
    Med. Res. Rev. (IF 9.791) Pub Date : 2001-10-19
    T M Willson,S A Jones,J T Moore,S A Kliewer

    Chemical genomics is the name we have given to the analysis of gene function through use of small molecule chemical tools. Orphan nuclear receptors are ideally suited to this technique of functional analysis, since their activity as transcription factors is regulated by small hydrophobic ligands. GW4064 is a potent and selective nonsteroidal ligand for the nuclear bile acid receptor FXR (NR1H4). Using GW4064 as a chemical tool, we have identified genes regulated by FXR in the liver, including those involved in bile acid synthesis and transport. We have also discovered that PXR (NR1I2) is a lithocholic acid receptor that controls the biosynthesis and metabolism of bile acids. Together FXR and PXR cooperate to control biliary and urinary bile acid excretion. These functions suggest that potent PXR and FXR ligands may offer a new approach to the treatment of cholestatic liver disease.

  • Tyrosine kinase inhibitors: from rational design to clinical trials.
    Med. Res. Rev. (IF 9.791) Pub Date : 2001-10-19
    P Traxler,G Bold,E Buchdunger,G Caravatti,P Furet,P Manley,T O'Reilly,J Wood,J Zimmermann

    Protein kinases play a crucial role in signal transduction as well as in cellular proliferation, differentiation, and various regulatory mechanisms. The inhibition of growth related kinases, especially tyrosine kinases, might provide new therapies for diseases such as cancer. The progress made in the crystallization of protein kinases has confirmed that the ATP-binding domain of tyrosine kinases is an attractive target for drug design. Three successful examples of drug design at Novartis using a tyrosine kinase as a molecular target are described. PKI166, a pyrrolo[2,3,-d]pyrimidine derivative, is a dual inhibitor of both the EGFR and the ErbB2 kinases. The compound entered clinical trials in 1999, based on its favorable preclinical profile: potent inhibition of EGF-mediated signalling in cells, in vivo antitumor activity in several EGFR overexpressing xenograft tumor models in nude mice, long-lasting inhibition of EGF-stimulated EGFR autophosphorylation in tumor tissue, good oral bioavailability in animals, and no prohibitive in vitro and in vivo toxicity findings. The anilino-phthalazine derivative PTK787/ZK222584 (Phase I, co-developed by Schering AG, Berlin) is a potent and selective inhibitor of both the KDR and Flt-1 kinases with interesting anti-angiogenic and pharmacokinetic properties (orally bioavailable). STI571 (Glivec, Gleevec), a phenylamino-pyrimidine derivative, is a potent inhibitor of the Abl tyrosine kinase, which is present in 95% of patients with chronic myelogenous leukemia (CML). The compound specifically inhibits proliferation of v-Abl and Bcr-Abl expressing cells (including cells from CML patients) and shows anti-tumor activity as a single agent in animal models at well-tolerated doses. Pharmacologically relevant concentrations are achieved in the plasma of animals (oral administration). Promising data from phase I and II clinical trials in CML patients (98% haematological response rate in Phase I) support the fact that the STI571 represents a new treatment modality for CML. In addition, potent inhibition of the PDGFR and c-Kit tyrosine kinases also indicates its possible clinical use in solid tumors.

  • Cyclin-dependent kinase inhibitors for treating cancer.
    Med. Res. Rev. (IF 9.791) Pub Date : 2001-10-19
    P L Toogood

    Cyclin dependent kinases (Cdks) are essential enzymes for the control of cell cycle progression. Inhibitors of cyclin-dependent kinases are anticipated to possess therapeutic utility against a wide variety of proliferative diseases, especially cancer. The field of published small molecule Cdk inhibitors is briefly reviewed here as background to a summary of work on a class of pyrido[2,3-d]pyrimidine Cdk inhibitors. Compounds from this class are described that display potency against cyclin D/Cdk4 up to IC(50) = 0.004 microM. Good to moderate selectivity for cyclin D/Cdk4 is also reported for compounds in this structural class. Structure-activity relationship data are presented for substitution at the C2 and N8 positions and these data are interpreted in the context of a binding model that is based on the Cdk2 crystal structure. A representative cyclin D/Cdk4 inhibitor (compound 56) is demonstrated to selectively inhibit the proliferation of an Rb(+) cell line vs. a matched Rb(-) cell line and to produce a distinct G(1) block consistent with cyclin D/Cdk4 inhibition in cells.

  • Modeling the 3D structure of GPCRs from sequence.
    Med. Res. Rev. (IF 9.791) Pub Date : 2001-10-02
    S Shacham,M Topf,N Avisar,F Glaser,Y Marantz,S Bar-Haim,S Noiman,Z Naor,O M Becker

    G-protein-coupled receptors (GPCRs) are a large and functionally diverse protein superfamily, which form a seven transmembrane (TM) helices bundle with alternating extra-cellular and intracellular loops. GPCRs are considered to be one of the most important groups of drug targets because they are involved in a broad range of body functions and processes and are related to major diseases. In this paper we present a new technology, named PREDICT, for modeling the 3D structure of any GPCR from its amino acid sequence. This approach takes into account both internal protein properties (i.e., the amino acid sequence) and the properties of the membrane environment. Unlike competing approaches, the new technology does not rely on the single known structure of rhodopsin, and is thus capable of predicting novel GPCR conformations. We demonstrate the capabilities of PREDICT in reproducing the known experimental structure of rhodopsin. In principle, PREDICT-generated models offer new opportunities for structure-based drug discovery towards GPCR targets.

  • Peptide hormone binding to G-protein-coupled receptors: structural characterization via NMR techniques.
    Med. Res. Rev. (IF 9.791) Pub Date : 2001-10-02
    D F Mierke,C Giragossian

    G-protein-coupled receptors (GPCRs) allow cells to respond to calcium, hormones, and neurotransmitters. Not surprisingly, they currently make up the largest family of validated drug targets. Rational drug design for molecular regulators targeting GPCRs has been limited to theoretical-based computational approaches. X-ray crystallography of intact GPCRs has provided the topological orientation of the seven transmembrane helices, but limited structural information of the extracellular and intracellular loops and protein termini. In this review we detail an NMR-based approach which provides the high-resolution structural features on the extracellular domains of GPCRs and the ligand/receptor complexes formed upon titration of the peptide hormone. The results provide important contact points and a high-resolution description of the ligand/receptor interactions, which may be useful for the rational design of therapeutic agents targeting GPCRs. Recent results from our investigation of the cholecystokinin peptide hormone system are used to highlight this approach.

  • Optimization of metabolic stability as a goal of modern drug design.
    Med. Res. Rev. (IF 9.791) Pub Date : 2001-10-02
    T N Thompson

    Metabolism and other pharmacokinetic (PK) studies have always played a critical role in helping to optimize the bioavailability and duration of action of new drugs thereby increasing their success rate. With the advent of automated combinatorial synthesis, high-throughput pharmacological testing, and the ability to create extensive databases in the past decade, drug discovery has undergone an amazing evolution. With the increased throughput of drug discovery, metabolism and other PK studies have evolved to keep pace. Often called "early ADME" studies, these studies are characterized by parallel processing and higher throughput than before. This article focuses on a particular class of early ADME (absorption, distribution mechanism, and excretion) studies known as "metabolic stability" studies. The theoretical basis for metabolic stability and its relationship to the concept of metabolic intrinsic clearance is briefly presented. Some key relationships between structure and metabolism are summarized. Several case studies from recent medicinal chemistry literature are reviewed to exemplify how metabolic stability studies influenced drug design and led to improvements in bioavailability and half-life. Finally, future trends in drug metabolism and analytical chemistry and how they may influence metabolic stability studies are reviewed.

  • Role of drug metabolism in drug discovery and development.
    Med. Res. Rev. (IF 9.791) Pub Date : 2001-10-02
    G N Kumar,S Surapaneni

    Metabolism by the host organism is one of the most important determinants of the pharmacokinetic profile of a drug. High metabolic lability usually leads to poor bioavailability and high clearance. Formation of active or toxic metabolites will have an impact on the pharmacological and toxicological outcomes. There is also potential for drug-drug interactions with coadministered drugs due to inhibition and/or induction of drug metabolism pathways. Hence, optimization of the metabolic liability and drug-drug interaction potential of the new chemical entities are some of the most important steps during the drug discovery process. The rate and site(s) of metabolism of new chemical entities by drug metabolizing enzymes are amenable to modulation by appropriate structural changes. Similarly, the potential for drug-drug interactions can also be minimized by appropriate structural modifications to the drug candidate. However, the optimization of the metabolic stability and drug-drug interaction potential during drug discovery stage has been largely by empirical methods and by trial and error. Recently, a lot of effort has been applied to develop predictive methods to aid the optimization process during drug discovery and development. This article reviews the role of drug metabolism in drug discovery and development.

  • Pharmacokinetics and its role in small molecule drug discovery research.
    Med. Res. Rev. (IF 9.791) Pub Date : 2001-10-02
    G R Jang,R Z Harris,D T Lau

    Pharmacokinetics (PK), which describes the disposition of a drug in the body, should be a primary consideration in the selection of a drug candidate, ultimately contributing to its eventual clinical success or failure. Accordingly, a sound understanding of PK concepts and an appreciation of the judicious use of PK and related (e.g., metabolism, transporter) data in drug discovery can be beneficial to those involved in the process. This review defines important PK parameters (e.g., clearance, volume of distribution, half-life), describes methods of PK data analysis (noncompartmental vs. compartmental) and provides an overview of additional concepts such as allometric scaling, PK/pharmacodynamic modeling, and nonlinear PK. Furthermore, the role and strategic use of PK screens in drug discovery are discussed.

  • Vancomycin, teicoplanin, and ramoplanin: synthetic and mechanistic studies.
    Med. Res. Rev. (IF 9.791) Pub Date : 2001-10-02
    D L Boger

    Vancomycin, teicoplanin, and ramoplanin are potent glycopeptide antibiotics that act by inhibiting bacterial cell wall biosynthesis. The former are used clinically as the antibiotics of last resort for the treatment of methicillin-resistant Staphylococcus aureus and the latter is a promising new antibiotic that is not susceptible to the emerging bacterial resistance to vancomycin and teicoplanin. A summary of our recent total synthesis of the vancomycin aglycon, our first and second generation total syntheses of the teicoplanin aglycon, and our progress on the total synthesis of the ramoplanins is presented. This work lays the foundation for ongoing structure-function studies on the antibiotics that may clarify or define their site and mechanism of action leading to the development of improved or reengineered antibiotics.

  • The ubiquitin-proteasome pathway and proteasome inhibitors.
    Med. Res. Rev. (IF 9.791) Pub Date : 2001-06-19
    J Myung,K B Kim,C M Crews

    The ubiquitin-proteasome pathway has emerged as a central player in the regulation of several diverse cellular processes. Here, we describe the important components of this complex biochemical machinery as well as several important cellular substrates targeted by this pathway and examples of human diseases resulting from defects in various components of the ubiquitin-proteasome pathway. In addition, this review covers the chemistry of synthetic and natural proteasome inhibitors, emphasizing their mode of actions toward the 20S proteasome. Given the importance of proteasome-mediated protein degradation in various intracellular processes, inhibitors of this pathway will continue to serve as both molecular probes of major cellular networks as well as potential therapeutic agents for various human diseases.

  • The active site of HIV-1 protease.
    Med. Res. Rev. (IF 9.791) Pub Date : 2001-06-19
    P P Mager

    The active site of the homodimeric HIV-1 protease includes six amino acids (triads AspThrGly found in each monomer) in amino acid positions 25 to 27 and 25' to 27'. Up to now, the role of Thr26 and Thr26', and Gly27 and Gly27', is unknown. It is hypothesized that strong hydrogen-bonding forces between the Thr26 and Thr26' residues stabilize the conformational state of the active site, and that the function of Gly27 and Gly27' is to accommodate and bind a substrate in a position in which the catalytic Asp25 and Asp25' carboxylate groups can attack the amide moiety of a substrate.

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