Redundancy in two major compound databases Drug. Discov. Today (IF 6.369) Pub Date : 2018-03-17 Dimitar Yonchev, Dilyana Dimova, Dagmar Stumpfe, Martin Vogt, Jürgen Bajorath
Public repositories of compounds and activity data are of prime importance for pharmaceutical research in academic and industrial settings. Major databases have evolved over the years. Their growth is accompanied by an increasing tendency toward data sharing. This is a positive development but not without potential problems. Using ChEMBL and PubChem as examples, we show that crosstalk between databases also leads to substantial data redundancy that might not be obvious. Redundancy is an important issue because it biases data analysis and knowledge extraction and leads to inflated views of available compounds, assays and activity data. Going forward it will be important to further refine data exchange and deposition criteria and make redundancy as transparent as possible.
Advances and applications of block-copolymer-based nanoformulations Drug. Discov. Today (IF 6.369) Pub Date : 2018-03-15 Vibhuti Agrahari, Vivek Agrahari
Block copolymers are widely utilized in the design of nanoformulations owing to their excellent physicochemical properties, flexible structure and functional chemistry. Advances in polymer synthetic approaches have significantly enhanced the ability to rationally design the block copolymers with tailor-made functionality and variable molecular weight. Hence, block copolymers have been extensively applied in the formulation of nanostructure materials. In this review, block copolymer classification, synthesis, characterization, stimuli-responsive behavior and nanostructure applications are summarized. Although block copolymers hold great potential for improving the therapeutic efficacy of drugs, a comprehensive delivery potential of these systems has not been fully exploited. Thus, an outlook on future developments on block-copolymer-based assemblies is further discussed.
A tumor multicomponent targeting chemoimmune drug delivery system for reprograming the tumor microenvironment and personalized cancer therapy Drug. Discov. Today (IF 6.369) Pub Date : 2018-03-15 Samaresh Sau, Katyayani Tatiparti, Hashem O. Alsaab, Sushil K. Kashaw, Arun K. Iyer
Nanomedicines can be multifunctional drug delivery agents for cancer therapies. However, they have faced several challenges in clinical trials owing to poor targeting ability, insufficient tumor penetration, difficulty in synthesis and scale up, and limited understanding of interactions between a tumor and nanoparticles. In this regard, tumor muticomponent targeting drug delivery systems are a rational approach for developing tumor-site-specific therapeutics. One of the goals is to arrive at a ready-to-configure, combinatorial, reagent-free click-chemistry-based tumor multicomponent targeting nanoparticle library. The nanoparticles can be co-loaded with drugs, genes and imaging agents, surface decorated with varying targeting ligands that can home to varying tumors and/or tumor multicomponents. This library of nanocarriers could be utilized for early tumor diagnosis and therapy based on individual patient needs for personalized medicine, with a high degree of success in the clinic.
Prediction of brain:blood unbound concentration ratios in CNS drug discovery employing in silico and in vitro model systems Drug. Discov. Today (IF 6.369) Pub Date : 2018-03-13 Houfu Liu, Kelly Dong, Wandong Zhang, Scott G. Summerfield, Georg C. Terstappen
Corrigendum to “Tocotrienls: the unsaturated sidekick shifting new paradigms in vitamin E therapeutics” [Drug Discov. Today 22 (December (12)) (2017) 1765–1781] Drug. Discov. Today (IF 6.369) Pub Date : 2018-03-07 M.M. Kanchi, M.K. Shanmugam, G. Rane, G. Sethi, A.P. Kumar
Quantitative metrics for drug target ligandability Drug. Discov. Today (IF 6.369) Pub Date : 2018-03-06 Sinisa Vukovic, David J. Huggins
Ligandability is a prerequisite for druggability and is a much easier concept to understand, model and predict because it does not depend on the complex pharmacodynamic and pharmacokinetic mechanisms in the human body. In this review, we consider a metric for quantifying ligandability from experimental data. We discuss ligandability in terms of the balance between effort and reward. The metric is evaluated for a standard set of well-studied drug targets – some traditionally considered to be ligandable and some regarded as difficult. We suggest that this metric should be used to systematically improve computational predictions of ligandability, which can then be applied to novel drug targets to predict their tractability.
Computational prediction of chemical reactions: current status and outlook Drug. Discov. Today (IF 6.369) Pub Date : 2018-03-03 Ola Engkvist, Per-Ola Norrby, Nidhal Selmi, Yu-hong Lam, Zhengwei Peng, Edward C. Sherer, Willi Amberg, Thomas Erhard, Lynette A. Smyth
Over the past few decades, various computational methods have become increasingly important for discovering and developing novel drugs. Computational prediction of chemical reactions is a key part of an efficient drug discovery process. In this review, we discuss important parts of this field, with a focus on utilizing reaction data to build predictive models, the existing programs for synthesis prediction, and usage of quantum mechanics and molecular mechanics (QM/MM) to explore chemical reactions. We also outline potential future developments with an emphasis on pre-competitive collaboration opportunities.
The neuroprotective role of the brain opioid system in stroke injury Drug. Discov. Today (IF 6.369) Pub Date : 2018-03-01 Bhuvaneshwar Vaidya, Ali Ehsan Sifat, Vardan T. Karamyan, Thomas J. Abbruscato
Novel neuroprotective therapies are desperately needed to improve neuronal recovery after ischemic stroke and extend the therapeutic window or offset some of the adverse effects of tissue-type plasminogen activator (tPA). These advances could provide a more effective and safe therapeutic regimen for patients with ischemic stroke. The opioid system has gained intense interest over the past fw years and is currently being investigated as a viable target for the pharmacological treatment of stroke. In this review, we focus on different opioid receptors (ORs) and their distribution in the central nervous system (CNS), and the effect of ischemic stroke on their redistribution. We also discus studies involving the use of the selective and nonselective and/or simultaneous targeting of ORs for neuroprotection during ischemic stroke.
Approved CAR T cell therapies: ice bucket challenges on glaring safety risks and long-term impacts Drug. Discov. Today (IF 6.369) Pub Date : 2018-03-01 Ping-Pin Zheng, Johan M. Kros, Jin Li
Two autologous chimeric antigen receptor (CAR) T cell therapies (Kymriah™ and Yescarta™) were recently approved by the FDA. Kymriah™ for the treatment of pediatric patients and young adults with refractory or relapse (R/R) B cell precursor acute lymphoblastic leukemia and Yescarta™ for the treatment of adult patients with R/R large B cell lymphoma. In common, both drugs are CD19-specific CAR T cell therapies lysing CD19-positive targets. Their dramatic efficacy in the short term has been highlighted by many media reports. By contrast, their glaring safety gaps behind the miracles remain much less addressed. Here, we focus on addressing the crucial challenges in relation to the gaps.
‘Bioexit’: navigating the policy and regulatory pathways for the biotechnology industry in a post-Brexit landscape Drug. Discov. Today (IF 6.369) Pub Date : 2018-03-01 Tim K. Mackey, John Annaloro
The withdrawal of the UK from the European Union (EU) is a complicated event. Although implications vary by industry, the biotechnology sector is especially vulnerable to the consequences of Brexit. Accordingly, here we evaluate potential repercussions under four post-Brexit political pathways: European Economic Area (EEA) affiliation (Norwegian Model); (negotiated bilateral access (Swiss Model); limited participation in EU Customs Union (Turkish Model); or independence under the World Trade Organization (WTO) designation. We conclude that all four pathways fail to protect the mutually beneficial UK–EU biotechnology relationship and that alternative pathways need to be explored. Accordingly, we outline a suite of policy mechanisms aimed at ensuring continued EU–UK regulatory synergy, with the central aim of ensuring access to biomedical innovations and ensuring patient safety.
The development of glutamate-based antidepressants is taking longer than expected Drug. Discov. Today (IF 6.369) Pub Date : 2018-03-01 Ricardo Garay, Carlos A. Zarate Jr., Icilio Cavero, Yong-Ku Kim, Thomas Charpeaud, Phil Skolnick
Highlights • Currently available antidepressants can take weeks to months to exert their therapeutic effects; during this latent period, patients are at an increased risk of suicide. Moreover, treatment-resistance is common in depression. Interest was therefore raised by preclinical and clinical studies demonstrating that the NMDAR (N-methyl-D-aspartate receptor)-antagonist ketamine produced rapid and marked antidepressant effects. However, the current use of intravenous, subanesthetic doses of ketamine in depression remains off-label, limited to a medical setting, and is burdened by other significant challenges. • Results from Phase II trials with selective NR2B NMDAR antagonists have largely been viewed as disappointing. However, failures to produce ketamine-like antidepressant effects may result from inadequate dosing. • In 2013, the Food and Drug Administration (FDA, USA) granted Breakthrough Therapy Designation (BTD) for intranasal esketamine (the S-enantiomer of ketamine) to treat major depressive disorder with imminent risk for suicide. A study comparing both ketamine enantiomers would be desirable because in several rodent models of depression, R-ketamine exhibited both a higher potency and longer-lasting antidepressant-like activity compared to the S-enantiomer (esketamine), although the latter has a four-fold higher affinity for NMDAR. • Esketamine and the glycineB-like functional partial agonist rapastinel are now being assessed in Phase III studies, with primary completion dates within the next two-three years. These results will be crucial for both development of these compounds and the exploration of other glutamatergic targets for the treatment of depression and other neuropsychiatric disorders.
Advances in glycosylation-mediated cancer-targeted drug delivery Drug. Discov. Today (IF 6.369) Pub Date : 2018-02-28 Lulu Cai, Zhipeng Gu, Jian Zhong, Di Wen, Guojun Chen, Lin He, Jun Wu, Zhen Gu
To enhance efficacy and safety, therapeutic antitumor agents are expected to target the desired locations where the ligand–receptor binding acts as a typical recognition approach. Among the various ligands, carbohydrates represent a crucial structure of tumor cell membranes and have been shown effective for cell-selective drug delivery. Recently, glycosylation-mediated therapeutic targeting strategies have been increasingly developed to form a variety of nanoscale delivery carriers. In this review, a variety of glycosylated drug delivery systems and their applications for cancer therapy have been surveyed. The future perspectives, including opportunities and challenges in this field, are also discussed.
Recent advances in brain tumor therapy: application of electrospun nanofibers Drug. Discov. Today (IF 6.369) Pub Date : 2018-02-27 Mohammad Norouzi
Despite much effort to treat glioblastoma multiforme (GBM), the median survival of patients has not significantly improved. The high rate of tumor recurrence after tumor resection and the blood–brain barrier (BBB) decrease treatment efficacy. Local drug delivery at the surgical resection site via implantable electrospun nanofibers not only circumvents the BBB, but can also reduce the rate of tumor recurrence. Nanofibers can provide the sustained release and high concentration of chemotherapeutics at the tumor vicinity, while decreasing their systemic exposure and toxicity. In another scenario, aligned nanofibers can mimic the topographical features of the brain extracellular matrix (ECM), which can be utilized for in vitro studies on GBM cell migration. This strategy is beneficial to investigate the interactions of tumor cells with this microenvironment, which has a dominant role in regulating tumor formation, progression, and metastasis.
The integrated stress response system in cardiovascular disease Drug. Discov. Today (IF 6.369) Pub Date : 2018-02-27 Diana Santos-Ribeiro, Laurent Godinas, Charles Pilette, Frédéric Perros
The integrated stress response system represents an ancillary, extremely conserved signalling pathway present in virtually all eukaryotic cells, which plays an important part in the pathophysiology of several disorders such as cancer and neurodegeneration. However, its role in the cardiovascular system remains largely elusive. Hence, this review aims to acknowledge recent findings regarding the action of the eIF2α kinases in the cardiovascular system and their role in the pathophysiology of related disorders.
Recent advances in near-infrared light-responsive nanocarriers for cancer therapy Drug. Discov. Today (IF 6.369) Pub Date : 2018-02-23 Ankit Saneja, Robin Kumar, Divya Arora, Sandeep Kumar, Amulya K. Panda, Sundeep Jaglan
In recent years, research has focused on the development of smart nanocarriers that can respond to specific stimuli. Among the various stimuli-responsive platforms for cancer therapy, near-infrared (NIR) light (700–1000 nm)-responsive nanocarriers have gained considerable interest because of their deeper tissue penetration capacity, precisely controlled drug release, and minimal damage towards normal tissues. In this review, we outline various therapeutic applications of NIR-responsive nanocarriers in drug delivery, photothermal therapy (PTT), photodynamic therapy (PDT), and bioimaging. We also highlight recent trends towards NIR-responsive combinatorial therapy and multistimuli-responsive nanocarriers for improving therapeutic outcomes.
Adaptive pathway development for Fabry disease: a clinical approach Drug. Discov. Today (IF 6.369) Pub Date : 2018-02-15 Yvonne Schuller, Maarten Arends, Simon Körver, Mirjam Langeveld, Carla E.M. Hollak
Fabry disease (FD) is a rare X-chromosome-linked lysosomal storage disorder. Although initial expectations of enzyme replacement therapy (ERT) were high, it is now clear that real-world effectiveness is disappointing and evidence gathering has been inadequate. In retrospect, development of ERT for FD had several shortcomings. Little convincing evidence on the effectiveness existed at time of authorization. Also, post-marketing evaluation failed to generate sufficient and relevant data for adequate evaluation on effectiveness. Adaptive pathways might have benefitted ERT development by: (i) involving healthcare professionals, patients, health technology assessment bodies and payers in the development process; (ii) iterative development, starting with initial authorization in classical males; (iii) a clear real-world data collection plan; (iv) an independent disease registry; and (v) prescription control.
Human-cell-derived organoids as a new ex vivo model for drug assays in oncology Drug. Discov. Today (IF 6.369) Pub Date : 2018-02-08 Miryam Mebarki, Annelise Bennaceur, Laurence Bonhomme-Faivre
In oncology, a 2D in vitro model of cancer cell lines is still widely used for large-scale drug screening. However, most promising candidates firstly identified by in vitro analysis tend to fail during the next steps of drug development. The generation of an ex vivo approach termed ‘organoid’ is emerging as a promising preclinical model to mimic human tumors more accurately. In this review, we focus on human-derived organoid use for anticancer drug screening. We describe the development of this new in vitro model, its use for anticancer agent assays and the advantages compared with the currently used 2D models. Finally, we discuss organoid limitations in the common use of this technology during preclinical studies.
Drug targeting of one or more aminoacyl-tRNA synthetase in the malarial parasite Plasmodium falciparum Drug. Discov. Today (IF 6.369) Pub Date : 2018-02-08 Manickam Yogavel, Rini Chaturvedi, Palak Babbar, Nipun Malhotra, Vitul Jain, Amit Sharma
Malaria remains a major infectious disease and, despite incidence reduction, it threatens resurgence in drug-resistant forms. Antimalarial drugs remain the mainstay of therapeutic options and hence there is a constant need to identify and validate new druggable targets. Plasmodium falciparum aminoacyl-tRNA synthetases (Pf-aaRSs) drive protein translation and are potent targets for development of next-generation antimalarials. Here, we detail advances made in structural-biology-based investigations in Pf-aaRSs and discuss their distribution of druggable pockets. This review establishes a platform for systematic experimental dissection of malarial parasite aaRSs as a new focus for sustained drug development efforts against malaria.
Cell membrane-coated nanocarriers: the emerging targeted delivery system for cancer theranostics Drug. Discov. Today (IF 6.369) Pub Date : 2018-02-06 Rajendran J.C. Bose, Ramasamy Paulmurugan, James Moon, Soo-Hong Lee, Hansoo Park
Cancer is a leading cause of death worldwide. The use of nanocarriers (NCs) has generated significant interest to improve cancer therapy by targeted delivery. However, conventional NCs in general lack specificity and have poor biodistribution, resulting in low efficacy in cancer therapy. To circumvent this problem, there has been an increasing focus on cancer cell membrane-coated NCs (CCMCNCs), which can deliver therapeutics directly to tumor cells. CCMCNCs comprise active cancer cell surface adhesive molecules combined with other functional proteins, and offer extended blood circulation with robust cell-specific targeting, ensuring enhanced intratumoral penetration and higher tumor-specific accumulation of NCs. In this review, we discuss the preparation, homologous targeting mechanisms, and application of CCMCNCs in targeted cancer therapy.
The roles of ions on bone regeneration Drug. Discov. Today (IF 6.369) Pub Date : 2018-02-03 Edward O’Neill, Guleid Awale, Leila Daneshmandi, Obum Umerah, Kevin W.-H. Lo
Bone scientists are actively investigating a range of methods to promote skeletal tissue regeneration. A review of recent literature has revealed that several ions are uniquely capable of inducing stem cell differentiation down desired lineages. There exists enormous promise for these ions to be used in bone regenerative medicine. Given that these ions can be released from biodegradable polymeric materials, their long-term delivery can be achieved through a variety of controlled-release strategies compared with the relatively few options available for expensive and fragile polypeptide-based growth factors. In this review, we highlight the developments in using ions in conjugation with biomaterials for bone regeneration.
Opportunities and pitfalls in clinical proof-of-concept: principles and examples Drug. Discov. Today (IF 6.369) Pub Date : 2018-02-03 Chao Chen
Clinical proof-of-concept trials crucially inform major resource deployment decisions. This paper discusses several mechanisms for enhancing their rigour and efficiency. The importance of careful consideration when using a surrogate endpoint is illustrated; situational effectiveness of run-in patient enrichment is explored; a versatile tool is introduced to ensure a high probability of pharmacological success; the benefits of dose-titration are revealed by simulation; and the importance of adequately scheduled observations is shown. The general process of model-based trial design and analysis is described and several examples demonstrate the value in historical data, simulation-guided design, model-based analysis and trial adaptation informed by interim analysis.
Research of novel anticancer agents targeting arginase inhibition Drug. Discov. Today (IF 6.369) Pub Date : 2018-02-03 Thanh-Nhat Pham, Bertrand Liagre, Corine Girard-Thernier, Céline Demougeot
Arginase plays an important part in l-arginine metabolism. This metalloenzyme also regulates polyamine biosynthesis, nitric oxide production and the T-cell-mediated immune response, which are all involved in the growth and control of cancer. Research over the past decades has reported arginase as an attractive target for cancer treatment, and inhibition of arginase could be a promising strategy for cancer therapy. Herein, we present the available data on the role of arginase in cancer development. The principal synthetic and natural arginase inhibitors are outlined and followed by their mechanism of action. Among them, some molecules have shown their anticancer effects. The perspectives of arginase inhibitors as new anticancer agents will be discussed.
Navigating albumin-based nanoparticles through various drug delivery routes Drug. Discov. Today (IF 6.369) Pub Date : 2018-02-03 Yeong L. Tan, Han K. Ho
Highlights • Albumin-based nanoparticles have been studied across many drug delivery routes. • The oral delivery of albumin-based nanoparticles is a potential exploratory route. As a natural polymer, albumin is well-received for being nontoxic, nonimmunogenic, biodegradable and biocompatible. Together with its targeting potential on specific cells, albumin-based nanoparticles appear as an effective carrier for various therapeutics. In recent years, there has been an increasing number of studies investigating the use of albumin-based nanoparticles across different administration routes. Although each route and target tissue presents a distinct anatomical and physiological profile that demands specific consideration, pharmaceuticals could still be delivered effectively via albumin-based nanoparticles. Therefore, this review discusses the features that warrant such applications across various delivery routes and explores their possibilities in other administration routes. The challenges associated with its use will also be elaborated to provide a holistic consideration to realise their clinical potentials.
The rise of deep learning in drug discovery Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-31 Hongming Chen, Ola Engkvist, Yinhai Wang, Marcus Olivecrona, Thomas Blaschke
Highlights • Deep learning technology has gained remarkable success. • We highlight the recent applications of deep learning in drug discovery research. • Some popular deep learning architectures are introduced in the current study. • Future development of deep learning in drug discovery is discussed. Over the past decade, deep learning has achieved remarkable success in various artificial intelligence research areas. Evolved from the previous research on artificial neural networks, this technology has shown superior performance to other machine learning algorithms in areas such as image and voice recognition, natural language processing, among others. The first wave of applications of deep learning in pharmaceutical research has emerged in recent years, and its utility has gone beyond bioactivity predictions and has shown promise in addressing diverse problems in drug discovery. Examples will be discussed covering bioactivity prediction, de novo molecular design, synthesis prediction and biological image analysis.
The diamond anniversary of tissue transglutaminase: a protein of many talents Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-31 William P. Katt, Marc A. Antonyak, Richard A. Cerione
Tissue transglutaminase (tTG) is capable of binding and hydrolyzing GTP, as well as catalyzing an enzymatic transamidation reaction that crosslinks primary amines to glutamine residues. tTG adopts two vastly different conformations, depending on whether it is functioning as a GTP-binding protein or a crosslinking enzyme. It has been shown to have important roles in several different aspects of cancer progression, making it an attractive target for therapeutic intervention. Here, we highlight many of the major findings involving tTG since its discovery 60 years ago, and describe recent drug discovery efforts that target specific activities or conformations of this unique protein.
Carbon dots: emerging theranostic nanoarchitectures Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-31 Vijay Mishra, Akshay Patil, Sourav Thakur, Prashant Kesharwani
Nanotechnology has gained significant interest from biomedical and analytical researchers in recent years. Carbon dots (C-dots), a new member of the carbon nanomaterial family, are spherical, nontoxic, biocompatible, and discrete particles less than 10 nm in diameter. Research interest has focused on C-dots because of their ultra-compact nanosize, favorable biocompatibility, outstanding photoluminescence, superior electron transfer ability, and versatile surface engineering properties. C-dots show significant potential for use in cellular imaging, biosensing, targeted drug delivery, and other biomedical applications. Here we discuss C-dots, in terms of their physicochemical properties, fabrication techniques, toxicity issues, surface engineering and biomedical potential in drug delivery, targeting as well as bioimaging.
Microfluidic platforms for modeling biological barriers in the circulatory system Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-31 Fang Yu, Nivasini D/O Selva Kumar, Deepak Choudhury, Lynette C. Foo, Sum Huan Ng
Recent advances in siRNA delivery for cancer therapy using smart nanocarriers Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-31 Penghui Zhang, Keli An, Xiaoman Duan, Hao Xu, Fei Li, Feng Xu
Small interfering RNAs (siRNAs) can selectively target and downregulate disease-causing genes, holding great promise in treating human diseases, especially malignant cancers. However, how to efficiently deliver siRNAs into target cell cytosol is a problem that has hindered their clinical application. Here, we review the recent strategies for siRNA delivery on the basis of smart nanocarriers by using stimuli-responsive materials. We highlight the rationales of how to design smart nanocarriers responsive to physiological and external stimuli to improve the delivery efficiency, targeting precision and gene silencing efficacy. Finally, we provide an outlook on the fundamental limitation for clinical translation of siRNA-based nanomedicine that should be overcome by the combination of chemistry, biology, material and medical science.
Nanomedicine as a potential approach to empower the new strategies for the treatment of preeclampsia Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-31 Lucie Valero, Khair Alhareth, Sophie Gil, Edouard Lecarpentier, Vassilis Tsatsaris, Nathalie Mignet, Thierry Fournier, Karine Andrieux
Preeclampsia is a serious pregnancy disorder characterized by the onset of high blood pressure and proteinuria. Although the understanding of the disease is increasing, it remains without treatment, other than the delivery of the baby and the placenta. This review sets out to discuss some new developments and strategies in the treatment of preeclampsia. We briefly review the current knowledge on the preeclamptic pathophysiology. We then examine the recent trends in preeclampsia treatment and, in particular, the tracks of potential therapeutic targets. Finally, we focus on the possibilities nanocarriers could offer in the management of preeclampsia. Indeed, nanocarriers could help to prevent transplacental passage and promote placental-specific drug delivery, thereby enhancing efficacy and improving safety. Tendencies are then drawn from the available studies on the optimal characteristics of a nanocarrier to deliver drugs to the placenta.
Thymoquinone-based nanotechnology for cancer therapy: promises and challenges Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-31 Farah Ballout, Zeina Habli, Omar Nasser Rahal, Maamoun Fatfat, Hala-Gali Muhtasib
Thymoquinone (TQ), the active ingredient of black seed, is a promising anticancer molecule that inhibits cancer cell growth and progression in vitro and in vivo. Despite the promising anticancer activities of TQ, its translation to the clinic is limited by its poor bioavailability and hydrophobicity. As such, we and others encapsulated TQ in nanoparticles to improve its delivery and limit undesirable cytotoxicity. These TQ-nanoparticle formulations showed improved anticancer and anti-inflammatory activities when compared with free TQ. Here, we provide an overview of the various TQ-nanoparticle formulations, highlight their superior efficacy and discuss up-to-date solutions to further enhance TQ bioavailability and anticancer activity, thus improving potential for clinical translation.
Facilitating the translation of nanomedicines to a clinical product: challenges and opportunities Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-31 Vibhuti Agrahari, Vivek Agrahari
There are numerous hurdles hindering the clinical translation of nanomedicines. The major challenges are: reproducible manufacturing and scale-up, availability of appropriate characterization methods, instability under in vivo environments, safety issues, poor understanding of the disease heterogeneity and patient preselection strategies, regulatory barriers and inadequate understanding of the biophysical and chemical interactions of nanoformulations. Technologies such as quality-by-design, process analytical techniques and microfluidics could significantly accelerate the translation of nanomedicines. However, these approaches require further learning and an adequate regulatory background. Overall, to achieve an efficient clinical translation, collaboration among academia, industry and regulatory bodies is required to ensure safe and effective nanomedicines. This review discusses the current challenges and opportunities to facilitate the translation of nanomedicines to a commercial product.
Methodologies for assessing the acceptability of oral formulations among children and older adults: a systematic review Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-31 Sejal R. Ranmal, Fiona O’Brien, Felipe Lopez, Fabrice Ruiz, Mine Orlu, Catherine Tuleu, Jennifer Walsh, Fang Liu
Acceptability of medicinal products in children and older populations is pivotal in ensuring adherence and therapeutic outcomes. This review systematically identifies studies reporting on formulation aspects of oral medications that affect their acceptability in these patient groups. Particular emphasis is placed on the evaluation of the methodologies employed in the studies. Sixty-eight studies were included for analysis, with 51 (75%) in children and 17 (25%) in older populations. The studies evaluated a range of oral formulations; however, the methodologies used differ considerably in participants’ characteristics, study settings, tools, acceptability definitions and criteria. It is evident that there is a lack of standardisation in study design as well as the assessment methods used in assessing acceptability of medicines in children and older populations.
Targeting Candida spp. to develop antifungal agents Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-19 Tânia P. Salci, Melyssa Negri, Ana K.R. Abadio, Terezinha I.E. Svidzinski, Érika S. Kioshima
Influenza A virus polymerase: an attractive target for next-generation anti-influenza therapeutics Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-12 Zhongxia Zhou, Tao Liu, Jian Zhang, Peng Zhan, Xinyong Liu
The influenza RNA-dependent RNA polymerase (RdRP) is conserved among different types of influenza virus, playing an important part in transcription and replication. In this regard, influenza RdRP is an attractive target for novel anti-influenza drug discovery. Herein, we will introduce the structural and functional information of influenza polymerase; and an overview of inhibitors targeting the PA endonuclease and PB2 cap-binding site is provided, along with the approaches utilized for identification of these inhibitors. The protein–protein interactions (PPIs) of the three polymerase subunits: PA, PB1 and PB2, are described based on the published crystal structures, and inhibitors targeting the PA–PB1 interaction are introduced briefly.
Safinamide: a new hope for Parkinson’s disease? Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-12 Fábio G. Teixeira, Miguel F. Gago, Paulo Marques, Pedro Silva Moreira, Ricardo Magalhães, Nuno Sousa, António J. Salgado
The loss of dopaminergic neurons (DAn) and reduced dopamine (DA) production underlies the reasoning behind the gold standard treatment for Parkinson’s disease (PD) using levodopa (L-DOPA). Recently licensed by the European Medicine Agency (EMA) and US Food and Drug Administration (FDA), safinamide [a monoamine oxidase B (MOA-B) inhibitor] is an alternative to L-DOPA; as we discuss here, it enhances dopaminergic transmission with decreased secondary effects compared with L-DOPA. In addition, nondopaminergic actions (neuroprotective effects) have been reported, with safinamide inhibiting glutamate release and sodium/calcium channels, reducing the excitotoxic input to dopaminergic neuronal death. Effects of safinamide have been correlated with the amelioration of non-motor symptoms (NMS), although these remain under discussion. Overall, safinamide can be considered to have potential antidyskinetic and neuroprotective effects and future trials and/or studies should be performed to provide further evidence for its potential as an anti-PD drug.
Mimicking the 3D biology of osteochondral tissue with microfluidic-based solutions: breakthroughs towards boosting drug testing and discovery Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-12 Mariana R. Carvalho, Rui Luís Reis, Joaquim Miguel Oliveira
The development of tissue-engineering (TE) solutions for osteochondral (OC) regeneration has been slowed by technical hurdles related to the recapitulation of their complex and hierarchical architecture. OC defects refer to damage of both the articular cartilage and the underlying subchondral bone. To repair an OC tissue defect, the complexity of the bone and cartilage must be considered. To help achieve this, microfluidics is converging with TE approaches to provide new treatment possibilities. Microfluidics uses precise micrometer-to-millimeter-scale fluid flows to achieve high-resolution and spatial and/or temporal control of the cell microenvironment, providing powerful tools for cell culturing. Herein, we overview the progress of microfluidics for developing 3D in vitro models of OC tissue, with a focus on cancer bone metastasis.
Designing an intuitive web application for drug discovery scientists Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-11 Nikiforos Karamanis, Miguel Pignatelli, Denise Carvalho-Silva, Francis Rowland, Jennifer A. Cham, Ian Dunham
Progress with covalent small-molecule kinase inhibitors Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-11 Zheng Zhao, Philip E. Bourne
With reduced risk of toxicity and high selectivity, covalent small-molecule kinase inhibitors (CSKIs) have emerged rapidly. Through the lens of structural system pharmacology, here we review this rapid progress by considering design strategies and the challenges and opportunities offered by current CSKIs.
On the glycosylation aspects of biosimilarity Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-11 László Hajba, Ákos Szekrényes, Beáta Borza, András Guttman
The recent expiration of several protein therapeutics opened the door for biosimilar development. Biosimilars are biologic medical products that are similar but not identical copies of already-authorized protein therapeutics. Critical quality attributes (CQA), such as post-translational modifications of recombinant biotherapeutics, are important for the clinical efficacy and safety of both the innovative biologics and their biosimilar counterparts. Here, we summarize biosimilarity CQAs, considering the regulatory guidelines and the statistical aspects (e.g., biosimilarity index) and then discuss glycosylation as one of the important attributes of biosimilarity. Finally, we introduced the ‘Glycosimilarity Index’, which is based on the averaged biosimilarity criterion.
Stem cells as vehicles and targets of nanoparticles Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-11 Sónia Pinho, Maria H. Macedo, Catarina Rebelo, Bruno Sarmento, Lino Ferreira
Modulation of endogenous adult stem cell niches represents a promising strategy for regeneration of tissues and to correct cell abnormalities, including cancer. Recent advances show the possibility to target endogenous stem cells or their progenies by using nanoparticles conjugated with specific biomolecules. In addition, the targeting of the stem cell niche can be accomplished by using stem cells loaded with nanoparticles. This review examines principles for the targeting of endogenous stem cells as well as factors for the modulation of stem cells.
The positive impacts of Real-World Data on the challenges facing the evolution of biopharma Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-11 John Wise, Angeli Möller, David Christie, Dipak Kalra, Elia Brodsky, Evelina Georgieva, Greg Jones, Ian Smith, Lars Greiffenberg, Marie McCarthy, Michael Arend, Olivier Luttringer, Sebastian Kloss, Steve Arlington
Demand for healthcare services is unprecedented. Society is struggling to afford the cost. Pricing of biopharmaceutical products is under scrutiny, especially by payers and Health Technology Assessment agencies. As we discuss here, rapidly advancing technologies, such Real-World Data (RWD), are being utilized to increase understanding of disease. RWD, when captured and analyzed, produces the Real-World Evidence (RWE) that underpins the economic case for innovative medicines. Furthermore, RWD can inform the understanding of disease, help identify new therapeutic intervention points, and improve the efficiency of research and development (R&D), especially clinical trials. Pursuing precompetitive collaborations to define shared requirements for the use of RWD would equip service-providers with the specifications needed to implement cloud-based solutions for RWD acquisition, management and analysis. Only this approach would deliver cost-effective solutions to an industry-wide problem.
Increasing mtDNA levels as therapy for mitochondrial optic neuropathies Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-11 Eduardo Ruiz-Pesini, Sonia Emperador, Ester López-Gallardo, Carmen Hernandez-Ainsa, Julio Montoya
Leber hereditary optic neuropathy (LHON) is a rare, inherited mitochondrial disease. No treatment has shown a clear-cut benefit on a clinically meaningful end-point. Primary open-angle glaucoma is a frequent, acquired optic neuropathy. Lowering intraocular pressure reduces disease progression. However, current methods to decelerate this progression are recognized as being inadequate. Therefore, there is a clear need to look for new therapeutic approaches. The growing evidence indicates that primary open-angle glaucoma can also be a mitochondrial optic neuropathy (MON). Several risk elements are common for both diseases and all of them decrease mitochondrial (mt)DNA content. Based on these susceptibility factors and their molecular mechanism, we suggest herein pharmacological therapies targeted to increase mtDNA levels, oxidative phosphorylation capability, and mitochondrial energy production as treatments for MONs.
Incorporating upper motor neuron health in ALS drug discovery Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-10 Ina Dervishi, P.Hande Ozdinler
Amyotrophic lateral sclerosis (ALS) is a complex disease, affecting the motor neuron circuitry. After consecutive failures in clinical trials for the past 20 years, edaravone was recently approved as the second drug for ALS. This generated excitement in the field and revealed the need to improve preclinical assays for continued success. Here, we focus on the importance and relevance of upper motor neuron (UMN) pathology in ALS, and discuss how incorporation of UMN survival in preclinical assays will improve inclusion criteria for clinical trials and expedite the drug discovery effort in ALS and related motor neuron diseases.
Peripheral modulation of the endocannabinoid system in metabolic disease Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-10 Nirajan Shrestha, James S.M. Cuffe, Dana S. Hutchinson, John P. Headrick, Anthony V. Perkins, Andrew J. McAinch, Deanne H. Hryciw
Dysfunction of the endocannabinoid system (ECS) has been identified in metabolic disease. Cannabinoid receptor 1 (CB1) is abundantly expressed in the brain but also expressed in the periphery. Cannabinoid receptor 2 (CB2) is more abundant in the periphery, including the immune cells. In obesity, global antagonism of overexpressed CB1 reduces bodyweight but leads to centrally mediated adverse psychological outcomes. Emerging research in isolated cultured cells or tissues has demonstrated that targeting the endocannabinoid system in the periphery alleviates the pathologies associated with metabolic disease. Further, peripheral specific cannabinoid ligands can reverse aspects of the metabolic phenotype. This Keynote review will focus on current research on the functionality of peripheral modulation of the ECS for the treatment of obesity.
The hitchhiker’s guide to the chemical-biological galaxy Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-09 Giulia Opassi, Alessandro Gesù, Alberto Massarotti
A bibliometric review of drug repurposing Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-09 Nancy C. Baker, Sean Ekins, Antony J. Williams, Alexander Tropsha
We have conducted a bibliometric review of drug repurposing by scanning >25 million papers in PubMed and using text-mining methods to gather, count and analyze chemical–disease therapeutic relationships. We find that >60% of the ∼35 000 drugs or drug candidates identified in our study have been tried in more than one disease, including 189 drugs that have been tried in >300 diseases each. Whereas in the majority of cases these drugs were applied in therapeutic areas close to their original use, there have been striking, and perhaps instructive, successful attempts of drug repurposing for unexpected, novel therapeutic areas.
Recent progress in the discovery of myeloid differentiation 2 (MD2) modulators for inflammatory diseases Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-09 Lingfeng Chen, Weitao Fu, Lulu Zheng, Yi Wang, Guang Liang
Myeloid differentiation protein 2 (MD2), together with Toll-like receptor 4 (TLR4), binds lipopolysaccharide (LPS) with high affinity, inducing the formation of the activated homodimer LPS-MD2-TLR4. MD2 directly recognizes the Lipid A domain of LPS, leading to the activation of downstream signaling of cytokine and chemokine production, and initiation of inflammatory and immune responses. However, excessive activation and potent host responses generate severe inflammatory syndromes such as acute sepsis and septic shock. MD2 is increasingly being considered as an attractive pharmacological target for the development of potent anti-inflammatory agents. In this Keynote review, we provide a comprehensive overview of the recent advances in the structure and biology of MD2, and present MD2 modulators as promising agents for anti-inflammatory intervention.
Present drug-likeness filters in medicinal chemistry during the hit and lead optimization process: how far can they be simplified? Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-09 Serge Mignani, João Rodrigues, Helena Tomas, Rachid Jalal, Parvinder Pal Singh, Jean-Pierre Majoral, Ram A. Vishwakarma
An update on the role of nanovehicles in nose-to-brain drug delivery Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-09 Yunhai Feng, Haisheng He, Fengqian Li, Yi Lu, Jianping Qi, Wei Wu
A quantitative analysis has cast doubt over the limited advantages provided by particles for nose-to-brain (NTB) drug delivery. Thus, it is imperative to identify the role of nanovehicles in NTB drug delivery. If nanocarriers are used merely as an option to improve various properties of the drugs or the formulations, it is difficult for them to outperform conventional formulations, such as solutions or gels. However, nanovehicles bring about special features, such as maintenance of the solubilized state of drugs, sustained or delayed release, and enhanced penetration because of surface modifications, all of which lead to enhanced NTB delivery efficiency.
Privileged portal metastasis of hepatocellular carcinoma in light of the coevolution of a visceral portal system and liver in the chordate lineage: a search for therapeutic targets Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-09 Vladimir M. Subbotin
Hepatocellular carcinoma (HCC) disseminates systemically, but metastases occur in distant organs in only a few patients, whereas HCC routinely metastasizes to liver and its vessels. HCC cells disseminate via hepatic veins, but portal veins are affected by metastasis more frequently than are hepatic veins, and correlates with poor prognosis. In this review, I suggest that privileged HCC portal metastasis occurs because of high levels of pancreatic family hormones and growth factors (PHGFs) in the portal blood. The analysis suggests that the appearance of the portal system carrying PHGFs in the evolution of invertebrate chordate (Amphioxus) led to the evolution of the liver in vertebrate; given that the portal pattern of HCC metastasis and selection of more-aggressive clones are PHGF dependent, PHGFs and their ligands constitute therapeutic targets.
Manipulating the epigenome for the treatment of disorders with thrombotic complications Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-09 Faith A.A. Kwa, Denise E. Jackson
The haemostatic system is tightly regulated to maintain homeostasis to avoid unwanted bleeding or thrombotic complications. Recent research has highlighted the importance of epigenetic changes, such as DNA methylation, histone modifications, and miRNA-based mechanisms, that alter gene expression. This can give rise to dysregulated haemostatic or vascular expressed molecules contributing to the development of thrombotic complications. Targeting these epigenetic changes could provide a new avenue for the treatment of pathological blood clots. However, the lack of tissue specificity warrants high-resolution genomic studies of the transcriptome and methylome that will reveal explicit epigenetic targets for the design of superior drugs with minimum off-target effects.
Unlocking the full potential of open innovation in the life sciences through a classification system Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-08 Niclas Nilsson, Timo Minssen
A common understanding of expectations and requirements is critical for boosting research-driven business opportunities in open innovation (OI) settings. Transparent communication requires common definitions and standards for OI to align the expectations of both parties. Here, we suggest a five-level classification system for OI models, reflecting the degree of openness. The aim of this classification system is to reduce contract negotiation complexity and times between two parties looking to engage in OI. Systematizing definitions and contractual terms for OI in the life sciences helps to reduce entry barriers and boosts collaborative value generation. By providing a contractual framework with predefined rules, science will be allowed to move more freely, thus maximizing the potential of OI.
Use of CRISPR/Cas9 gene-editing tools for developing models in drug discovery Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-08 Gulzar Ahmad, Mansoor Amiji
Clustered regularly interspaced short palindromic repeat/CRISPR-associated 9 (CRISPR/Cas9) enables targeted genome engineering. The simplicity of this system, its facile engineering, and amenability to multiplex genes make it the system of choice for many applications. This system has revolutionized our ability to carry out gene editing, transcription regulation, genome imaging, and epigenetic modification. In this review, we discuss the discovery of CRISPR/Cas9, its mechanism of action, its application in medicine and animal model development, and its delivery. We also highlight how the CRISPR/Cas9 system can affect the next generation of drugs by accelerating the identification and validation of high-value targets. The generation of precision disease models through this system will provide a rapid avenue for functional drug screening.
Light-triggerable formulations for the intracellular controlled release of biomolecules Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-08 Miguel M. Lino, Lino Ferreira
New therapies based on the use of biomolecules [e.g., proteins, peptides, and non-coding (nc)RNAs] have emerged during the past few years. Given their instability, adverse effects, and limited ability to cross cell membranes, delivery systems are required to fully reveal their biological potential. Sophisticated nanoformulations responsive to light offer an excellent opportunity for the controlled release of these biomolecules, enabling the control of timing, duration, location, and dosage. In this review, we discuss the design principles for the delivery of biomolecules, in particular proteins and RNA-based therapeutics, by light-triggerable formulations. We further discuss the opportunities offered by these formulations in terms of endosomal escape, as well as their limitations.
Pharmaceutical nanocrystals: production by wet milling and applications Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-08 Maria Malamatari, Kevin M.G. Taylor, Stavros Malamataris, Dennis Douroumis, Kyriakos Kachrimanis
Nanocrystals are regarded as an important nanoformulation approach exhibiting advantages of increased dissolution and saturation solubility with chemical stability and low toxicity. Nanocrystals are produced in the form of nanosuspensions using top-down (e.g., wet milling or high pressure homogenization) and bottom-up methods (e.g., antisolvent precipitation). Wet milling is a scalable method applicable to drugs with different physicochemical and mechanical properties. Nanocrystalline-based formulations, either as liquid nanosuspensions or after downstream processing to solid dosage forms, have been developed as drug delivery systems for various routes of administration (i.e., oral, parenteral, pulmonary, ocular, and dermal). In this review, we summarize and discuss the features, preparation methods, and therapeutic applications of pharmaceutical nanocrystals, highlighting their universality as a formulation approach for poorly soluble drugs.
NCp7: targeting a multitask protein for next-generation anti-HIV drug development part 2. Noncovalent inhibitors and nucleic acid binders Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-08 Nunzio Iraci, Oriana Tabarrini, Claudio Santi, Luca Sancineto
Nucleocapsid protein 7 (NCp7) represents a viable target not yet reached by the currently available antiretrovirals. It is a small and highly basic protein, which is essential for multiple stages of the viral replicative cycle, with its structure preserved in all viral strains, including clinical isolates. NCp7 can be inhibited covalently, noncovalently and by shielding the nucleic acid (NA) substrates of its chaperone activity. Although covalent NCp7 inhibitors have already been detailed in the first part of this review series, the focus here is based on noncovalent and NA-binder inhibitors and on the analysis of the NCp7 3D structure to deliver fruitful insights for future drug design strategies.
Macromolecule nanotherapeutics: approaches and challenges Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-08 Puneet Tyagi, Jose Luis Santos
Mechanism of nanoparticle-induced hypersensitivity in pigs: complement or not complement? Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-08 János Szebeni
A recent study on nanoparticle-induced hypersensitivity reactions in pigs showed robust pulmonary intravascular macrophage clearance of Polybead® carboxylate microspheres in mediating the adverse cardiopulmonary distress, irrespective of the ability of these particles to activate the Complement (C) system in vitro. Focusing on this observation, this article highlights the controversies in projecting in vitro C assay data to in vivo conditions and applying data on polystyrene particles to therapeutic nanopharmaceuticals. Based on overwhelming evidence of a role of anaphylatoxins in hypersensitivity reactions, the need to further explore the role of C activation in the reported and other reactions is highlighted. C-activation-related and C-independent pseudoallergies (CARPA and CIPA) can proceed simultaneously, as outlined by the ‘double-hit’ hypothesis.
Phage-derived lysins as potential agents for eradicating biofilms and persisters Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-08 Umender Sharma, Aradhana Vipra, Shankaramurthy Channabasappa
Bacterial biofilms are highly resistant to the action of antibiotics. Presence of persisters, phenotypically resistant populations of bacterial cells, is thought to contribute toward recalcitrance of biofilms. The phage-derived lysins, by virtue of their ability to cleave the peptidoglycan of bacterial cells in an enzymatic manner, have the unique ability to kill dormant cells. Several lysins have shown potent antibiofilm activity in vitro. The fact that lysins have shown better efficacy than conventional drugs in animal models of endocarditis and other infections involving biofilms suggests that the lysins can potentially be developed against difficult-to-treat bacterial infections.
Ligandomics: a paradigm shift in biological drug discovery Drug. Discov. Today (IF 6.369) Pub Date : 2018-01-08 Wei Li, Iok-Hou Pang, Mario Thiego F. Pacheco, Hong Tian
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