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  • TGFβ and BMPRII signalling pathways in the pathogenesis of pulmonary arterial hypertension
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-12-07
    Birger Tielemans, Marion Delcroix, Catharina Belge, Rozenn Quarck

    Pulmonary arterial hypertension (PAH) is a severe condition characterised by remodelling of precapillary pulmonary arteries sometimes associated with mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene. Even in the absence of BMPR2 mutations, increased transforming growth factor (TGF)β receptor signalling and decreased BMPRII signalling have been shown to contribute to PAH pathogenesis. In this Keynote, we review the potential mechanisms by which the imbalance of BMP/TGFβ signalling contributes to endothelial dysfunction, vascular remodelling, inflammation and disordered angiogenesis in PAH. Additionally, we highlight how currently used drugs cab influence BMP/TGFβ signalling. Finally, we browse the newly developed therapeutic approaches targeting BMPRII and TGFβ signalling pathways by focusing on preclinical studies and clinical trials.

  • Efficient drug discovery by rational lead hybridization based on crystallographic overlay
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-12-04
    Shuo Zhang, Jian Zhang, Ping Gao, Lin Sun, Yuning Song, Dongwei Kang, Xinyong Liu, Peng Zhan

    In this review, we provide an overview of recent applications of crystallographic overlay-based molecular structure hybridization of lead compounds as a rational strategy for efficient drug discovery, with selected examples, and briefly discuss its advantages compared with other ligand-based methodologies.

  • Pharmaceutical cocrystals: from serendipity to design to application
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-12-03
    Oisin N. Kavanagh, Denise M. Croker, Gavin M. Walker, Michael J. Zaworotko

    The field of pharmaceutical cocrystals has reached a tipping point, particularly because cocrystals can improve the physicochemical properties of drugs without compromising their therapeutic benefit. Accounts of cocrystal investigations in the literature started in earnest in 2003 and patent applications soon followed. The frequency of both has steadily accelerated, demonstrating an enhanced understanding of the design, characterisation, and manufacture of cocrystals and heightened interest from industry. Indeed, there were four new product approvals from 2014 to 2017 and more are in the pipeline. Here, we review all marketed drug products that are based upon pharmaceutical cocrystal drug substances, starting with the first recorded example, Beta-Chlor® in 1963, with a particular emphasis on their discovery, rationale for use, and market impact.

  • Behavior, experience, skill, and training: a four-pillar framework and tool for career development in science
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-12-03
    Rebecca Ashkenazy

    Technical expertise and a spirit of inquiry serve as cornerstones for a career in science. Within that career, there are multiple pathways across disciplines, therapeutic areas, and sectors. To optimize career planning, I showcase here a career development framework that integrates four pillars: behavior, experience, skill, and training (BEST). This framework encompasses interrelated elements that are crucial for career progression and reflects evolving priorities in today’s network-oriented environment. Individuals can also leverage the framework as a tool to support short- and long-term career planning.

  • Essential oils: from prevention to treatment of skin cancer
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-11-30
    P.S. Pavithra, Alka Mehta, Rama S. Verma

    The increasing incidence of cutaneous malignancies signifies the need for multiple treatment options. Several available reviews have emphasized the potential role of various botanical extracts and naturally occurring compounds as anti-skin-cancer agents. Few studies relate to the role of chemoprevention and therapeutic activity of essential oils (EOs) and EO components. The present review summarizes an overview of chemopreventive, anti-melanoma and anti-nonmelanoma activities of EOs from various plants and EO components in in vitro and in vivo models with special emphasis on skin cancer. Also, the mechanisms by which EOs and EO components exert their effects to induce cell death are presented.

  • The drug repurposing landscape from 2012 to 2017: evolution, challenges, and possible solutions
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-12-01
    Prasanthi Polamreddy, Nandu Gattu

    As the name suggests, drug repurposing is a strategy to identify new therapeutic uses for marketed drugs, discontinued and/or shelved drugs, and drug candidates currently in clinical development. Although not a recent concept, drug repurposing has gained momentum over the past few years and several drugs have been successfully repurposed. Here, we summarize the drug repurposing landscape from 2012 to 2017, with a major focus on repurposed drugs, collaborative opportunities, and funding opportunities specific to drug repurposing projects. Along with success stories, we also highlight the challenges and limitations associated with drug repurposing.

  • Recent advances in pharmaceutical dosage forms and devices using additive manufacturing technologies
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-11-29
    Christos I. Gioumouxouzis, Christina Karavasili, Dimitrios G. Fatouros

    The era of ‘one-size-fits-all’ treatment approaches is becoming history for pharmaceutical manufacturing with the future encountering a revolution in drug development through the introduction of additive manufacturing technologies. The innovative elements of this disruptive technology will affect all shareholders of the pharmaceutical chain from the industrial sector to the dispensing facilities and, ultimately, the patient end-user. In this review, we provide an overview of the most recent advances in dosage forms and devices using additive manufacturing technologies, along with the regulatory landscape framing the development and safety requirements for 3D-printed drug products before entering the pharmaceutical market.

  • Contemporary medicinal-chemistry strategies for the discovery of selective butyrylcholinesterase inhibitors
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-11-29
    Lanlan Jing, Gaochan Wu, Dongwei Kang, Zhongxia Zhou, Yuning Song, Xinyong Liu, Peng Zhan

    Butyrylcholinesterase (BChE) is considered a promising drug target for the treatment of moderate to severe Alzheimer's disease (AD). Here, we review medicinal-chemistry strategies that are currently available for the discovery of selective BChE inhibitors.

  • Copies of nonbiological complex drugs: generic, hybrid or biosimilar?
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-08-04
    Paolo Rocco, Umberto M. Musazzi, Silvia Franzè, Paola Minghetti
  • Turning straw into gold: building robustness into gene signature inference
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-08-04
    Wilson Wen Bin Goh, Limsoon Wong

    Reproducible and generalizable gene signatures are essential for clinical deployment, but are hard to come by. The primary issue is insufficient mitigation of confounders: ensuring that hypotheses are appropriate, test statistics and null distributions are appropriate, and so on. To further improve robustness, additional good analytical practices (GAPs) are needed, namely: leveraging existing data and knowledge; careful and systematic evaluation of gene sets, even if they overlap with known sources of confounding; and rigorous testing of inferred signatures against as many published data sets as possible. Here, using a re-examination of a breast cancer data set and 48 published signatures, we illustrate the value of adopting these GAPs.

  • New leads for drug repurposing against malaria
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-08-09
    Nila Madassary Pazhayam, Jyoti Chhibber-Goel, Amit Sharma

    Malaria is threatening a resurgence because of drug resistance against frontline artemisinin-based combination therapies (ACTs). This necessitates the development of alternate routes for malaria treatment. Here, we present a refined focus on US Food and Drug Administration (FDA)-approved over-the-counter (OTC) drugs that could be repurposed. We analyzed growth inhibition data for Plasmodium falciparum and Plasmodium berghei in the context of 189 and 37 drugs (total of 226), respectively. Of these, our analyses revealed 18 currently used drugs that would be suitable for further development as potential antimalarials. Eight identified drugs share enzymatic targets between the human host and the malaria parasite, providing a platform for mechanistic and drug selectivity studies that could provide optimized leads as next-generation antimalarials.

  • Nanoengineered delivery systems for cancer imaging and therapy: recent advances, future directions and patent evaluation
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-08-16
    Ghazal Nabil, Ketki Bhise, Samaresh Sau, Mohamed Atef, Hossny A. El-Banna, Arun K. Iyer

    Cancer is the second-highest cause of death worldwide. Several therapeutic approaches, such as conventional chemotherapy, antibodies and small-molecule inhibitors and nanotherapeutics, have been employed in battling cancer. Among them, nanotheranostics is an example of successful personalized medicine bearing the dual role of early diagnosis and therapy to cancer patients. In this review, we focus on various types of theranostic polymer and metal nanoparticles for their roles in cancer therapy and imaging concerning their limitations and future applications, such as dendritic cell cancer vaccination, gene delivery, T cell activation and immune modulation. Some of the recorded patent applications and clinical trials are illustrated and the impact of the biological microenvironment on the biodistribution and accumulation of nanoparticles is also discussed.

  • Advancing precision medicine with personalized drug screening
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-08-17
    Kirill Gorshkov, Catherine Z. Chen, Raisa E. Marshall, Nino Mihatov, Yong Choi, Dac-Trung Nguyen, Noel Southall, Kevin G. Chen, John K. Park, Wei Zheng

    Personalized drug screening (PDS) of approved drug libraries enables rapid development of specific small-molecule therapies for individual patients. With a multidisciplinary team including clinicians, researchers, ethicists, informaticians and regulatory professionals, patient treatment can be optimized with greater efficacy and fewer adverse effects by using PDS as an approach to find remedies. In addition, PDS has the potential to rapidly identify therapeutics for a patient suffering from a disease without an existing therapy. From cancer to bacterial infections, we review specific maladies addressed with PDS campaigns. We predict that PDS combined with personal genomic analyses will contribute to the development of future precision medicine endeavors.

  • Cnidarian peptide neurotoxins: a new source of various ion channel modulators or blockers against central nervous systems disease
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-08-27
    Qiwen Liao, Yu Feng, Binrui Yang, Simon Ming-Yuen Lee

    Cnidaria provide the largest source of bioactive peptides for new drug development. The venoms contain enzymes, potent pore-forming toxins and neurotoxins. The neurotoxins can immobilize predators rapidly when discharged via modifying sodium-channel-gating or blocking the potassium channel during the repolarization stage. Most cnidarian neurotoxins remain conserved under the strong influence of negative selection. Neuroactive peptides targeting the central nervous system through affinity with ion channels could provide insight leading to drug treatment of neurological diseases, which arise from ion channel dysfunctions. Although marine resources offer thousands of possible peptides, only one peptide derived from Cnidaria: ShK-186, also named dalazatide, has reached the pharmaceutical market. This review focuses on neuroprotective agents derived from cnidarian neurotoxic peptides.

  • Computational modeling for formulation design
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-11-28
    Chetan Hasmukh Mehta, Reema Narayan, Usha Y. Nayak

    Formulation design is an important phase in the development of new drug s. However, this process at an experimental level requires exhaustive experimental work. Excipient selection, prediction of solubility, encapsulation efficiency, release patterns, drug absorption, stability, and mechanism of nanoparticle formation are some of the essential steps in formulation design. The use of various computational tools, including quantitative structure–activity relationships (QSARs), molecular modeling, molecular mechanics, discrete element modeling, finite element method, computational fluid dynamics, and physiologically based pharmacokinetics (PBPK) modeling, help in the identification of drug product inadequacies and to recommend avenues for understanding complex formulation design in less time with lower investment. Here, we focus on computational modeling tools used in formulation design and its applications.

  • Characterization of circulating tumor cells as a reflection of the tumor heterogeneity: myth or reality?
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-11-26
    Hannah Brown, Marta Tellez-Gabriel, Pierre-François Cartron, François Vallette, Marie-Francoise Heymann, Dominique Heymann

    The current main goal of diagnostic medicine is to detect crucial events in ‘infinitely’ small samples. The key question now is how to determine whether the rare cell events isolated and characterized from these samples reliably reflect the disease and heterogeneity of the tumor. In this review, we provide a short overview of the most recent methods developed for the isolation and characterization of rare cell events in clinical practice, with a specific focus on circulating tumor cells. We discuss the biological value to studying these cells at the single cell level and how these rare cell events can reflect tumor heterogeneity. The potential biomedical applications are also critically discussed in light of precision medicine.

  • Phosphinic acids: current status and potential for drug discovery
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-11-24
    Moaz M. Abdou, Paul M. O’Neill, Eric Amigues, Magdalini Matziari

    Phosphinic acid derivatives exhibit diverse biological activities and a high degree of structural diversity, rendering them a versatile tool in the development of new medicinal agents. Pronounced recent progress, coupled with previous research findings, highlights the impact of this moiety in medicinal chemistry. Here, we highlight the most important breakthroughs made with phosphinates with a range of pharmacological activities against many diseases, including anti-inflammatory, anti‐Alzheimer, antiparasitic, antihepatitis, antiproliferative, anti-influenza, anti-HIV, antimalarial, and antimicrobial agents. We also provide the current status of the corresponding prodrugs, drug-delivery systems, and drug applications of phosphinic acids in the clinical stage

  • Analysis of solvent-exposed and buried co-crystallized ligands: a case study to support the design of novel protein–protein interaction inhibitors
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-11-22
    Daniela Trisciuzzi, Orazio Nicolotti, Maria A. Miteva, Bruno O. Villoutreix

    Molecular descriptors have been used to characterize and predict the functions of small molecules, including inhibitors of protein–protein interactions (iPPIs). Such molecules are valuable to investigate disease pathways and as starting points for drug discovery endeavors. iPPIs tend to bind at the surface of macromolecules and the design of such compounds remains challenging. Here, we report on our investigation of a pool of interpretable molecular descriptors for solvent-exposed and buried co-crystallized ligands. Several descriptors were found to be significantly different between the two classes and were further exploited using machine-learning approaches. This work could open new perspectives for the rational design of focused libraries enriched in a new type of small drug-like molecule that could be used to prevent PPIs.

  • Artificial intelligence in drug development: present status and future prospects
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-11-22
    Kit-Kay Mak, Mallikarjuna Rao Pichika

    Artificial intelligence (AI) uses personified knowledge and learns from the solutions it produces to address not only specific but also complex problems. Remarkable improvements in computational power coupled with advancements in AI technology could be utilised to revolutionise the drug development process. At present, the pharmaceutical industry is facing challenges in sustaining their drug development programmes because of increased R&D costs and reduced efficiency. In this review, we discuss the major causes of attrition rates in new drug approvals, the possible ways that AI can improve the efficiency of the drug development process and collaboration of pharmaceutical industry giants with AI-powered drug discovery firms.

  • Meeting the discovery challenge of drug-resistant infections: progress and focusing resources
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-11-23
    Gordon Dougan, Chris Dowson, John Overington,

    Following multiple warnings from governments and health organisations, there has been renewed investment, led by the public sector, in the discovery of novel antimicrobials to meet the challenge of rising levels of drug-resistant infection, particularly in the case of resistance to antibiotics. Initiatives have also been announced to support and enable the antibiotic discovery process. In January 2018, the Medicines Discovery Catapult, UK, hosted a symposium: Next Generation Antibiotics Discovery, to consider the latest initiatives and any remaining challenges to inform and guide the international research community and better focus resources to yield a novel class of antibiotic.

  • Advancing nonclinical innovation and safety in pharmaceutical testing
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-11-20
    Elizabeth J. Baker, Nancy A. Beck, Ellen L. Berg, Helene D. Clayton-Jeter, P. Charukeshi Chandrasekera, J. Lowry Curley, Bruce A. Donzanti, Lorna C. Ewart, Jane M. Gunther, J. Gerry Kenna, Edward L. LeCluyse, Michael N. Liebman, Catherine L. Pugh, Paul B. Watkins, Kristie M. Sullivan

    Nonclinical tests are considered crucial for understanding the safety of investigational medicines. However, the effective translation from nonclinical to human application is limited and must be improved. Drug development stakeholders are working to advance human-based in vitro and in silico methods that might be more predictive of human efficacy and safety in vivo because they enable scientists to model the direct interaction of drugs with human cells, tissues, and biological processes. Here, we recommend test-neutral regulations; increased funding for development and integration of human-based approaches; support for existing initiatives that advance human-based approaches; evaluation of new approaches using human data; establishment of guidelines for procuring human cells and tissues for research; and additional training and educational opportunities in human-based approaches for XXXXX.

  • A review of non-invasive insulin delivery systems for diabetes therapy in clinical trials over the past decade
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-11-19
    Najma Easa, Raid Alany, Mark Carew, Anil Vangala

    At present, the main form of insulin administration is the invasive subcutaneous (s.c.) route and, for many patients, this means managing their glucose levels with multiple daily injections, which is both painful and difficult to administer chronically. To increase patient compliance, products are slowly reaching the market that are more patient friendly, such as the insulin patch-pump systems, including Omnipod and V-Go, but also the inhaled-insulin Afrezza® and the buccal insulin Oral-lyn™. In this review, we outline the history of insulin, the various options that are currently available in practice for insulin delivery, and the non-invasive delivery systems that have entered the different stages of clinical trials over the past decade.

  • Accelerating pharmaceutical structure-guided drug design: a successful model
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-11-15
    Lisa J. Keefe, Vincent S. Stoll

    The impact and value of structure-based drug design to pharmaceutical discovery across the industry are now undeniable, with many break-through therapies on the market that are structure based in nature. Enabling the structural research is the Industrial Macromolecular Crystallography Association-Collaborative Access Team (IMCA-CAT), formed over 25 years ago as a world-class research facility at the synchrotron at Argonne National Laboratory. What makes IMCA-CAT unique is the strategy of the founding consortium to comprehensively provide for the evolving needs of industry in one facility. This includes year-round high-quality data, capabilities that match target portfolios, throughput and capacity that are never limiting, and unfailing security. Here, we illuminate the unique capabilities offered by IMCA-CAT and instruct how all industrial organizations can access this facility.

  • Pharmacophore-based models for therapeutic drugs against phosphorylated tau in Alzheimer’s disease
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-11-16
    Jangampalli Adi Pradeepkiran, Arubala P. Reddy, P. Hemachandra Reddy

    Phosphorylated tau (P-tau) has received much attention in the field of Alzheimer’s disease (AD), as a potential therapeutic target owing to its involvement with synaptic damage and neuronal dysfunction. The continuous failure of amyloid β (Aβ)-targeted therapeutics highlights the urgency to consider alternative therapeutic strategies for AD. The present review describes the latest developments in tau biology and function. It also explains abnormal interactions between P-tau with Aβ and the mitochondrial fission protein Drp1, leading to excessive mitochondrial fragmentation and synaptic damage in AD neurons. This article also addresses 3D pharmacophore-based drug models designed to treat patients with AD and other tauopathies.

  • Gut reaction: impact of systemic diseases on gastrointestinal physiology and drug absorption
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-11-16
    Grace B. Hatton, Christine M. Madla, Sarit C. Rabbie, Abdul W. Basit

    It was in 400 BC that Hippocrates reportedly stated that “death sits in the colon”. The growth in our knowledge of the intestinal microbiome and the gut–brain axis, their function and imbalance, has distinctly uncovered the complex relationship between the gut to disease predisposition and development, heralding the problem and the solution to disease pathology. Human studies of new drug molecules are typically performed in healthy volunteers and their specific disease indication. Approved drugs, however, are used by patients with diverse disease backgrounds. Here, we review the current literature of the gastrointestinal tract reacting to systemic disease pathology that elicits physiological and functional changes that consequently affect oral drug product performance.

  • A new generation of antidepressants: an update on the pharmaceutical pipeline for novel and rapid-acting therapeutics in mood disorders based on glutamate/GABA neurotransmitter systems
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-11-14
    Samuel T. Wilkinson, Gerard Sanacora

    Mood disorders represent the largest cause of disability worldwide. The monoaminergic deficiency hypothesis, which has dominated the conceptual framework for researching the pathophysiology of mood disorders and the development of novel treatment strategies, cannot fully explain the underlying neurobiology of mood disorders. Mounting evidence collected over the past two decades suggests the amino acid neurotransmitter systems (glutamate and GABA) serve central roles in the pathophysiology of mood disorders. Here, we review progress in the development of compounds that act on these systems as well as their purported mechanisms of action. We include glutamate-targeting drugs, such as racemic ketamine, esketamine, lanicemine (AZD6765), traxoprodil (CP-101,606), EVT-101, rislenemdaz (CERC-301/MK-0657), AVP-786, AXS-05, rapastinel (formerly GLYX-13), apimostinel (NRX-1074/AGN-241660), AV-101, NRX-101, basimglurant (RO4917523), decoglurant (RG-1578/RO4995819), tulrampator (CX-1632/S-47445), and riluzole; and GABA-targeting agents, such as brexanolone (SAGE-547), ganaxolone, and SAGE-217.

  • The essentiality of drug targets: an analysis of current literature and genomic databases
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-11-13
    Xiao Ji, Deepak K. Rajpal, Johannes M. Freudenberg

    Essential genes encode proteins thought to be crucial for the survival of an organism. However, the role of essential genes in human disease and their suitability as drug targets is less clear. Here, we use a recent catalog of nearly 9000 known essential and nonessential genes to evaluate their involvement as therapeutic targets in human diseases. We find that essential genes are more likely than nonessential genes to play a part in specific therapeutic areas such as cardiovascular diseases and neoplasms. We also find significant differences between essential and nonessential genes among protein classes relevant to drug discovery. Taken together, our analyses suggest that the essentiality status of a potential new target is an important consideration in drug discovery.

  • Role of MIF and D-DT in immune-inflammatory, autoimmune, and chronic respiratory diseases: from pathogenic factors to therapeutic targets
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-11-13
    Sven Günther, Paolo Fagone, Gaël Jalce, Atanas Atanasov, Christophe Guignabert, Ferdinando Nicoletti

    Macrophage migration inhibitory factor (MIF) is a protein that acts as a cytokine-, enzyme-, endocrine- and chaperon-like molecule. It binds to the cell-surface receptor CD74 in association with CD44, which activates the downstream signal transduction pathway. In addition, MIF acts also as a noncognate ligand for C-X-C chemokine receptor type 2(CXCR2), CXCR4, and CXCR7. Recently, D-dopachrome tautomerase (D-DT), a second member of the MIF superfamily, was identified. From a pharmacological and clinical point of view, the nonredundant biological properties of MIF and D-DT anticipate potential synergisms from their simultaneous inhibition. Here, we focus on the role of MIF and D-DT in human immune-inflammatory, autoimmune, and chronic respiratory diseases, providing an update on the progress made in the identification of specific small-molecule inhibitors of these proteins.

  • Strategies for brain-targeting liposomal delivery of small hydrophobic molecules in the treatment of neurodegenerative diseases
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-11-08
    Zi-Ying Wang, Sravan Gopalkrishnashetty Sreenivasmurthy, Ju-Xian Song, Jingyi Liu, Min Li

    Neurodegenerative diseases (NDs), including Alzheimer’s disease (AD) and Parkinson’s disease (PD), threaten the health of an ever-growing number of older people worldwide; so far, there are no effective cures. Significant efforts have been devoted to developing new drugs for NDs in recent years, and some small molecules have been shown to be promising in preclinical studies. However, the major challenge for brain-targeting drugs is how to efficiently deliver the drugs across the blood–brain barrier (BBB) to desired targets. To address this issue, liposomal delivery systems have proved to be ideal carriers for neuroprotective small molecules. Here, we summarize recent advances in the brain-targeting liposomal delivery of small hydrophobic molecules (SHMs) and propose strategies for developing liposomal SHMs as disease-modifying neurotherapeutics for NDs.

  • Growing synergy of nanodiamonds in neurodegenerative interventions
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-11-05
    Jackson Saraf, Kiran Kalia, Pallab Bhattacharya, Rakesh Kumar Tekade
  • Interplay between hereditary and environmental factors to establish an in vitro disease model of keratoconus
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-11-05
    Subhadeep Roy, Saumya Yadav, Tanushree Dasgupta, Shikha Chawla, Radhika Tandon, Sourabh Ghosh

    Keratoconus (KC) is a bilateral corneal dystrophy and a multifactorial, multigenic disorder with an etiology involving a strong environmental component and complex inheritance patterns. The underlying pathophysiology of KC is poorly understood because of potential crosstalk between genetic–epigenetic variants possibly triggered by the environmental factors. Here, we decode the etiopathological basis of KC using genomic, transcriptomic, proteomic and metabolic approaches. The lack of relevant models that accurately imitate this condition has been particularly limiting in terms of the effective management of KC. Tissue-engineered in vitro models of KC could address this need and generate valuable insights into its etiopathology for the establishment of disease models to accelerate drug discovery.

  • Therapeutic potential of endogenous stem cells and cellular factors for scar-free skin regeneration
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-11-05
    Shibashish Giri, Hans-Günther Machens, Augustinus Bader

    Injured human skin fails to regenerate, resulting in scar formation. Annually, 100 million new skin-scarring incidents, occurring as a result of surgery, disease, burns, or sports-related damage, remain untreated. Here, we review knowledge gained from scar-free experimental animal models that have natural regenerative mechanisms for scar-free skin recovery. We also focus on the unique role of endogenous stem cells and other cellular and molecular factors, including the balance of the transforming growth factor-beta (TGF-β) pathway in the context of human skin regeneration. This new strategy opens a new window in drug development for scar-free skin regeneration treatments in both the clinical and cosmetic practice settings.

  • Evolution of commercially available compounds for HTS
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-11-03
    Dmitriy M. Volochnyuk, Sergey V. Ryabukhin, Yurii Moroz, Olena Savych, Alexander Chuprina, Dragos Horvath, Yuliana Zabolotna, Alexandre Varnek, Duncan B. Judd

    Over recent years, an industry of compound suppliers has grown to provide drug discovery with screening compounds: it is estimated that there are over 16 million compounds available from these sources. Here, we review the chemical space covered by suppliers’ compound libraries (SCL) in terms of compound chemophysical properties, novelty, diversity, and quality. We examine the feasibility of compiling high-quality vendor-based libraries avoiding complicated, expensive compound management activity, and compare the resulting libraries to the ChEMBL data set. We also consider how vendors have responded to the evolving requirements for drug discovery.

  • Microtransplantation of human brain receptors into oocytes to tackle key questions in drug discovery
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-11-03
    Ruud Zwart, Francesca Mazzo, Emanuele Sher

    It is important in drug discovery to demonstrate that activity of novel drugs found by screening on recombinant receptors translates to activity on native human receptors in brain areas affected by disease. In this review, we summarise the development and use of the microtransplantation technique. Native receptors are reconstituted from human brain tissues into oocytes from the frog Xenopus laevis where they can be functionally assessed. Oocytes microtransplanted with hippocampal tissue from an epileptic patient were used to demonstrate that new antiepileptic agents act on receptors in diseased tissue. Furthermore, frozen post-mortem human tissues were used to show that drugs are active on receptors in brain areas associated with a disease; but not in areas associated with side effects.

  • Micro- and nano-formulations for bioprinting and additive manufacturing
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-11-01
    Guillaume Bouguéon, Tina Kauss, Bérangère Dessane, Philippe Barthélémy, Sylvie Crauste-Manciet

    Recent developments in bioprinting have enabled an optimized formulation of bioinks by incorporating pharmaceuticals into cell-containing gel matrices. The proof-of-printability of a variety of forms has been provided, such as particles and fibers in the nanometric or micrometric range like dendrimers or micelles, although this is still lacking for some (liposomes for example). Resulting composite bioinks have the advantage of (i) improving cell growth and differentiation, (ii) delivering active molecules or (iii) improving mechanical properties of bioinks, printed scaffolds or the printing process. Improvement of these properties brings bioprinting one step forward toward clinical applications. Applications are reviewed for each field of improvements.

  • FoxO1–miRNA interacting networks as potential targets for mitochondrial diseases
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-10-24
    Prasanth Puthanveetil

    Mitochondrial homeostasis is important for the health and well-being of organ systems and organisms. Mitochondrial dysfunction is known to be the cause and consequence of metabolic diseases, including obesity, diabetes, cancer, neurodegeneration, cerebrovascular, and cardiovascular disease. For cardiovascular tissue, which relies mostly on oxidative phosphorylation, the role of mitochondria is inevitable. Rather than being biomarkers of mitochondrial health, miRNAs are now known as bioregulators of this important feature. Recent studies have shown a close interaction between Forkhead box other 1 (FoxO1) transcription factors and miRNAs in the cardiovascular system. These interactions have also been shown to regulate mitochondrial homeostasis. In this review, I highlight how understanding FoxO1 and miRNA interacting networks could enable us to limit mitochondrial dysfunction and associated pathologies.

  • The power of combining phenotypic and target-focused drug discovery
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-10-22
    Ralf Heilker, Uta Lessel, Daniel Bischoff

    A fierce dispute has arisen between the supporters of phenotypic and target-focused screening regarding which path grants the higher probability of successful drug development. A chance to reconcile these two approaches lies in successful target deconvolution (TD) after phenotypic screens. But, despite the panoply of available in vitro TD methods, the task of matching a phenotypically active compound with a biomolecular target remains challenging. Consequently, this review details the latest developments of in silico techniques that expedite TD. Ultimately, the deconvoluted target allows us to reap the benefits of the phenotypic and target-focused approaches.

  • Using molecular-mimicry-inducing pathways of pathogens as novel drug targets
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-10-23
    Anjali Garg, Bandana Kumari, Neelja Singhal, Manish Kumar

    Several microbial pathogens cause autoimmune diseases in humans by exhibiting molecular mimicry with the host proteins. However, the contribution of autoimmunity in microbial pathogenesis has not been evaluated critically. Clinical and experimental observations have supported and corroborated that autoimmunity was a fundamental process underlying pathology of human tuberculosis bacteria. In the current review, we propose novel drug targets based on a pathogen’s molecular-mimicry-inducing proteins. The process for identification of drug targets has been explained using Mycobacterium tuberculosis as a model organism. The procedure described here can be applied for repurposing other known drugs and/or discovery of novel therapeutics against other pathogenic bacteria that exhibit molecular mimicry with the host’s proteins.

  • Accomplishments and challenges in stem cell imaging in vivo
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-10-17
    Rajendran J.C. Bose, Robert F. Mattrey

    Stem cell therapies have demonstrated promising preclinical results, but very few applications have reached the clinic owing to safety and efficacy concerns. Translation would benefit greatly if stem cell survival, distribution and function could be assessed in vivo post-transplantation, particularly in patients. Advances in molecular imaging have led to extraordinary progress, with several strategies being deployed to understand the fate of stem cells in vivo, for example using magnetic resonance, scintigraphy, PET, ultrasound and optical imaging. Here, we review the recent advances, challenges and future perspectives and opportunities in stem cell tracking and functional assessment, as well as the advantages and challenges of each imaging approach.

  • Advances in particle shape engineering for improved drug delivery
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-10-17
    Yiwei Yang, Di Nie, Yuan Liu, Miaorong Yu, Yong Gan

    Spherical particles such as liposomes and microspheres are the most common and extensively applied drug vehicles. However, researchers have come to realize the superiority of nonspherical nanoparticles. Actually, in human bodies red blood cells, gut biotics and many well-known pathogens have distinct shapes. It can be reasonably inferred that particle shape plays a pivotal part in human bodies. In this review, we summarize the recent studies about the effect of shape on delivery processes such as cellular uptake, tissue penetration and biodistribution. The underlying mechanisms that are relevant to the phenomena revealed, owing to experimental and computational modern techniques, will be addressed, and we shall provide future perspectives on particle design to improve the efficacy of drug delivery.

  • Can lifecycle management safeguard innovation in the pharmaceutical industry?
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-10-17
    Stefanie Hering, Brigitta Loretz, Thomas Friedli, Claus-Michael Lehr, Frank Stieneker

    The pharmaceutical industry invests enormous amounts of resources ( > €1 billion and >10 years) in the development of new products. External factors such as intensifying foreign competition and greater regulatory demands can negatively affect the profit margin, whereas the R&D productivity diminishes. To stay competitive and to maintain high R&D capabilities for developing new medicinal products, companies must make smart investment decisions to maximize their return on investment. Consequently, the entire lifecycle of a medicinal product must be effectively managed to ensure a sustained development through commercialization. This review critically assesses the current situation and the associated management strategies throughout the lifecycle of a medicinal product.

  • Artificial intelligence and its potential in oncology
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-10-17
    Vaishali Y. Londhe, Bhavya Bhasin

    The two main branches associated with Artificial Intelligence (AI) in medicine are virtual and physical. The virtual component includes machine learning (ML) and algorithms, whereas physical AI includes medical devices and robots for delivering care. AI is used successfully in tumour segmentation, histopathological diagnosis, tracking tumour development, and prognosis prediction. CURATE.AI, developed at the National University of Singapore, is a platform that automatically decides the optimum dose of drugs for a durable response, allowing the patient to resume a completely normal life. With the involvement of technology multinationals, such as Google and Microsoft, in AI and healthcare in association with leading healthcare companies, the future of AI in healthcare looks very promising.

  • Trends in interorganizational transactions in personalized medicine development
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-10-16
    Tomohiro Makino, Shintaro Sengoku, Shuichi Ishida, Kota Kodama

    Personalized medicine is an innovative concept that allows patients with a validated companion diagnosis (CoDx) to receive treatment using the most suitable drug. Currently, a major movement in the pharmaceutical industry involves the integrated use of multiple resources from external sources. To ascertain preferable interorganizational collaborations and their suitable exits, we compared the related transactions in personalized and nonpersonalized cancer drugs. We found that there were significantly more of some alliance deals in personalized medicine, and that market licenses, one of the exits, were well correlated with other alliances only in personalized medicine. Furthermore, four types of collaboration mode were identified, and more active collaborations with external partners were found to lead to more successful outcomes in personalized medicine development.

  • Targeting VEGF–neuropilin interactions: a promising antitumor strategy
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-10-11
    Kewen Peng, Ying Bai, Qihua Zhu, Bin Hu, Yungen Xu

    Inhibition of vascular endothelial growth factor (VEGF) or its corresponding receptor (VEGFR) has been validated as an efficacious antiangiogenetic approach for cancer treatment. More recently, neuropilins (NRPs), the essential coreceptors for VEGF, have also been shown to have a significant role in VEGF signaling. Given the multifaceted effects of VEGF–NRP interactions on tumor initiation and progression, the exploration of new chemical entities that selectively block these interactions has recently attracted considerable interest as a novel antitumor strategy. Here, we summarize the biological functions of VEGF–NRP interactions in tumor biology, analyze the structural basis for these interactions, and present a detailed discussion of the development of the NRP antagonists reported so far.

  • Towards the development of human immune-system-on-a-chip platforms
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-10-09
    Alessandro Polini, Loretta L.del Mercato, Adriano Barra, Yu Shrike Zhang, Franco Calabi, Giuseppe Gigli

    Organ-on-a-chip (OoCs) platforms could revolutionize drug discovery and might ultimately become essential tools for precision therapy. Although many single-organ and interconnected systems have been described, the immune system has been comparatively neglected, despite its pervasive role in the body and the trend toward newer therapeutic products (i.e., complex biologics, nanoparticles, immune checkpoint inhibitors, and engineered T cells) that often cause, or are based on, immune reactions. In this review, we recapitulate some distinctive features of the immune system before reviewing microfluidic devices that mimic lymphoid organs or other organs and/or tissues with an integrated immune system component.

  • Peptide-based therapeutics: quality specifications, regulatory considerations, and prospects
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-10-06
    Shruti Rastogi, Shatrunajay Shukla, M. Kalaivani, Gyanendra Nath Singh

    Exquisite selectivity, remarkable efficacy, and minimal toxicity are key attributes inherently assigned to peptides, resulting in increased research interest from the pharmaceutical industry in these peptide-based therapeutics (PbT). Pharmacopoeias are used to develop authoritative standards for PbT by providing standard specifications and test methods. Nevertheless, a lack of harmonization in test procedures adopted for PbT in the latest editions of Pharmacopoeias has been observed. Adoption of a harmonized monograph could increase further the interest of the global pharmaceutical industry in PbTs. Here, we provide an overview of pharmacopoeial methodologies and specifications commonly observed in PbT monographs and highlight the main differences among the pharmacopoeias in terms of the active pharmaceutical ingredients that they focus on. We also address the prospects for PbT to mature as a new therapeutic niche.

  • Application of nanotechnology to improve the therapeutic benefits of statins
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-10-05
    Shahla Korani, Mitra Korani, Samira Bahrami, Thomas P. Johnston, Alexandra E . Butler, Maciej Banach, Amirhossein Sahebkar

    Hyperlipidemia is defined as an elevated level of lipids and lipoproteins in the blood and is considered to be a significant risk factor for accelerating the process of atherosclerosis and, consequently, cardiovascular disease. The level of cholesterol, especially low-density lipoprotein cholesterol (LDL-C), is commonly elevated in hyperlipidemia and represents the primary therapeutic target. Statins are a group of drugs that function by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and are extremely efficacious in reducing elevated LDL-C in the serum and preventing atherosclerotic cardiovascular disease. However, statins have some limitations, such as poor aqueous solubility, low oral absorption, and, consequently, limited bioavailability when administered by the oral route. The field of nanotechnology is now well developed and some of these newer nanotechnology strategies offer systems with enhanced aqueous solubility of the statin, increased absorption, bioavailability, and controlled release of the statin at the site of administration. Here, we discuss nano-sized drug delivery systems to enhance the therapeutic potential of statins.

  • Design strategies for chemical-stimuli-responsive programmable nanotherapeutics
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-10-05
    Muhammad Gulfam, Fitsum Feleke Sahle, Tao L. Lowe

    Chemical-stimuli-responsive nanotherapeutics have gained great interest in drug delivery and diagnosis applications. These nanotherapeutics are designed to respond to specific internal stimuli including pH, ionic strength, redox, reactive oxygen species, glucose, enzymes, ATP and hypoxia for site-specific and responsive or triggered release of payloads and/or biomarker detections. This review systematically and comprehensively addresses up-to-date technological and design strategies, and challenges nanomaterials to be used for triggered release and sensing in response to chemical stimuli.

  • Implications of human induced pluripotent stem cells in metabolic disorders: from drug discovery toward precision medicine
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-10-04
    Agustin Cota-Coronado, P. Berenice Ramírez-Rodríguez, Eduardo Padilla-Camberos, Nestor F. Diaz, Jose M. Flores-Fernández, Daniela Avila-Gonzalez, N. Emmanuel Diaz-Martinez

    Human induced pluripotent stem cells (hiPSCs) enable in vitro high-throughput pharmacological screening assays of diseased tissue. Together with recent genome-wide association studies (GWAS), hiPSCs enable the identification of key mutations for the development of effective treatments based on precise drugs. In concert with CRISPR/Cas9 systems, hiPSC technology can reveal therapeutic targets in metabolic disorders. The ex vivo CRISPR correction of autologous patient-derived hiPSCs has led to the development of replacement cell therapies, providing better patient prognoses.

  • The future R&D landscape in non-alcoholic steatohepatitis (NASH)
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-10-03
    Darcey Black, Sarah Brockbank, Simon Cruwys, Kim Goldenstein, Peter Hein, Bob Humphries

    Nonalcoholic steatohepatitis (NASH) is emerging as a major public health issue for the 21 st century and is associated with significant liver-related morbidity and mortality. At present, there are no approved drug therapies for NASH. Consequently, NASH has become the focus of significant public and private research and development. In this review, we highlight the research and development (R&D) challenges and opportunities in this emerging therapeutic area. In particular, we consider the impact of the development of new biomarker strategies on clinical trial execution and design, and the positioning of single and combination therapies in future approaches to the treatment of NASH.

  • Antithrombotic P2Y12 receptor antagonists: recent developments in drug discovery
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-10-03
    Younis Baqi, Christa E. Müller

    The P2Y12 receptor is one of eight known P2Y receptor subtypes, and belongs to the G-protein-coupled receptor (GPCR) family. The P2Y12 receptor is highly expressed on blood platelets and in the brain. Potent, selective, peripherally acting antagonists for the P2Y12 receptor are used clinically as antithrombotic drugs. Several different scaffolds have been identified as P2Y12 receptor antagonists, including irreversibly acting thienotetrahydropyridines (prodrugs), and reversible competitive antagonists, including adenine nucleotide analogs, piperazinyl-glutamate-quinolines, −pyridines, and −pyrimidines, and anthraquinone derivatives. Here, we provide an overview of the different scaffolds that have been developed as P2Y12 receptor antagonists, some of which have become important therapeutics.

  • Basic and practical concepts of radiopharmaceutical purification methods
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-09-29
    Sajjad Molavipordanjani, Vladimir Tolmachev, Seyed Jalal Hosseinimehr
  • Targeting intrinsically disordered proteins at the edge of chaos
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-09-29
    Hao Ruan, Qi Sun, Weilin Zhang, Ying Liu, Luhua Lai

    Intrinsically disordered proteins or intrinsically disordered regions (IDPs or IDRs) are those that do not fold into defined tertiary structures under physiological conditions. Given their prevalence in various diseases, IDPs are attractive therapeutic targets. However, because of the dynamic nature of the IDP structure, conventional structure-based drug design methods cannot be directly applied. Thanks to recent progress in understanding the mechanisms underlying IDP and ligand interactions, computational strategies for IDP-targeted rational drug discovery are emerging. Here, we summarize recent developments in computational IDP drug design strategies and their successful applications, analyze the typical properties of reported IDP-binding compounds (iIDPs), and discuss the major challenges ahead as well as possible solutions.

  • Considerations for implementing an informatics system to support biologics drug discovery
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-09-26
    Andrew P. LeBeau

    A comprehensive, well-functioning and scientifically aware informatics environment is of the utmost importance in supporting effective drug discovery programs. However, implementing such a system can, without a carefully crafted and enacted strategy, be a disruptive and time-consuming process, fraught with risks of cost overruns and the potential to end up with a system that ultimately does not meet the ever-evolving needs of the organization. In this review, using our experience from the software provider perspective, we discuss how a drug discovery organization should approach the task of selecting an informatics system to support its research discovery programs. We focus on biologics drug discovery because: (i) in general, biologics informatics is less mature than small-molecule discovery; (ii) there is a great deal of activity in biologics drug discovery, from new biologics-only companies to established small-molecule companies extending into biologics programs; and (iii) by their nature, biologics can be more challenging than small molecules to support, owing to the size, complexity and diversity of biologics entities. These factors make decisions about which system(s) to implement even more challenging.

  • Fungal immunomodulatory proteins: characteristic, potential antitumor activities and their molecular mechanisms
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-09-25
    Qi-Zhang Li, Yu-Zhang Zheng, Xuan-Wei Zhou

    During recent decades, >30 fungal immunomodulatory proteins (FIPs) have been found in a range of mushrooms and other fungi. Various pharmacological functions of FIPs have become important in the discovery and development of new drugs. In this review, we discuss some important factors, focusing on the use of amino acid sequence data to predict structural and physicochemical properties. We also discuss pharmacologic activities and possible mechanisms of the proteins with a focus on antitumor activities. Numerous other questions must also be addressed before FIPs can be widely accepted and used as antitumor agents.

  • Factors and situations influencing the value of patient preference studies along the medical product lifecycle: a literature review
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-09-26
    Eline van Overbeeke, Chiara Whichello, Rosanne Janssens, Jorien Veldwijk, Irina Cleemput, Steven Simoens, Juhaeri Juhaeri, Bennett Levitan, Jürgen Kübler, Esther de Bekker-Grob, Isabelle Huys
  • Small molecules for fat combustion: targeting thermosensory and satiety signals in the central nervous system
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-09-21
    Jingxin Liu, Ligen Lin

    Brown adipose tissue (BAT) dissipates fatty acids as heat to maintain body temperature in cold environments. The existence of BAT and beige cells in human adults supplies a promising weight-reduction therapy. The central thermogenic regulation descends through an excitatory neural pathway from the hypothalamus, medullar and spine toward BAT. This sympathoexcitatory thermogenic circuit is controlled by GABAergic (γ-aminobutyric acid) signaling from the thermoregulatory center in the preoptic area and the satiety center in the ventromedial nucleus of the hypothalamus. This review summarizes recent research progress in thermogenic regulators targeting thermosensory and satiety signals in the central nervous system, and speculates on their potential as antiobesity agents.

  • Biosimilar medicines used for cancer therapy in Europe: a review
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-09-19
    Sofia B. Santos, José M. Sousa Lobo, Ana C. Silva

    This article provides an updated review of the biosimilar medicines approved for cancer therapy in the European Union (EU). First we discuss the most relevant aspects for the development and approval of biosimilar medicines. We then present the oncological biosimilar drugs currently used, which include epoetins (alpha and zeta), filgrastim, and monoclonal antibodies (rituximab, trastuzumab and bevacizumab). Among the clinical applications of biosimilar medicines, cancer therapy remains the main target area and more approved biosimilars are expected over the next few years, providing cost-effective drugs to more patients. Furthermore, comprehensive pharmacovigilance studies are going on, monitoring the marketed biosimilars, and providing more feasible information to clinicians regarding the safety and efficacy of these medications.

  • Functionalizing bioinks for 3D bioprinting applications
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-09-19
    Azraa Parak, Priyamvada Pradeep, Lisa C. du Toit, Pradeep Kumar, Yahya E. Choonara, Viness Pillay
  • Safety differentiation: emerging competitive edge in drug development
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-09-19
    Marianne Uteng, Laszlo Urban, Dominique Brees, Patrick Y. Muller, Gerd A. Kullak-Ublick, Page Bouchard, Gervais Tougas, Salah-Dine Chibout

    With increasing expectations to provide evidence of drug efficacy, safety, and cost-effectiveness, best-in-class drugs are a major value driver for the pharmaceutical industry. Superior safety is a key differentiation criterion that could be achieved through better risk:benefit profiles, safety margins, fewer contraindications, and improved patient compliance. To accomplish this, comparative safety assessments using innovative and adaptive nonclinical and clinical outcome-based approaches should be undertaken, and continuous strategic adjustments must be made as the risk:benefit profiles evolve. Key success criteria include scientific expertise and integration between all disciplines during the full extent of the drug development process.

Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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