Review, News & Views, Perspectives, Hypotheses and Analyses

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  • Since the introduction of insulin almost a century ago, more than 80 peptide drugs have been approved for a wide range of diseases. This Perspective summarizes trends in peptide drug discovery, emphasizing lessons from earlier approaches as well as emerging strategies such as integrated venomics and peptide-display libraries. It also analyses the remaining challenges and the pharmaceutical landscape in which peptide drugs are particularly valuable.

    • Markus Muttenthaler
    • Glenn F. King
    • Paul F. Alewood
  • Academic research has a key role in identifying new drug targets, but to lead to new drugs this research must progress to testing drug candidates in clinical trials, which are typically conducted by industry. This Perspective presents a framework to support academic scientists and funders in prioritizing target assessment activities and in defining a critical path to reach scientific goals as well as goals related to licensing, partnering with industry or initiating clinical trials.

    • Christoph H. Emmerich
    • Lorena Martinez Gamboa
    • Michael J. Parnham
  • Phase 0 approaches, including microdosing, evaluate subtherapeutic exposures to novel drugs, potentially enabling safer, cheaper and quicker first-in-human studies. Here, Burt et al. discuss the fundamentals and applications of phase 0 approaches, highlight the potential advantages of their application in drug development and address the associated limitations.

    • Tal Burt
    • Graeme Young
    • Yuichi Sugiyama
  • Dendritic cell vaccines have been widely investigated as a type of cancer immunotherapy, but their promise has not yet been realized. Kandalaft and colleagues propose that a prime and boost approach — primed with either standard therapies or dendritic cell vaccines and boosted with a personalized synthetic vaccine — could help fulfil the potential of such vaccines. They discuss improvements in dendritic cell vaccines that have enabled prime–boost approaches, as well as challenges for adoption.

    • Alexandre Harari
    • Michele Graciotti
    • Lana E. Kandalaft
  • Oral delivery of peptide therapeutics could have benefits for treatment adherence, but it faces barriers related to the structural organization and physiological function of the gastrointestinal tract. This article highlights strategies to overcome these barriers and discusses experience with oral peptides that have reached clinical trials, including the recent landmark approval of an oral formulation of semaglutide for the treatment of type 2 diabetes.

    • Daniel J. Drucker
  • Artificial intelligence (AI) tools are increasingly being applied in drug discovery. This article presents the views of a group of international experts on the ‘grand challenges’ in small-molecule drug discovery with AI, including obtaining appropriate data sets, generating new hypotheses, optimizing in a multi-objective manner, reducing cycle times and changing the research culture.

    • Petra Schneider
    • W. Patrick Walters
    • Gisbert Schneider
  • Current preclinical models poorly predict the potential of a new drug candidate to cause drug-induced liver injury (DILI) in humans. Here, Park and colleagues discuss current understanding of the mechanisms mediating DILI and, through an academic–industry collaboration, propose a roadmap for the development of predictive preclinical models of human DILI.

    • Richard J. Weaver
    • Eric A. Blomme
    • B. Kevin Park
  • Small molecules that induce targeted protein degradation by the ubiquitin–proteasome system, such as proteolysis-targeting chimeras (PROTACs), are attracting great interest as a new therapeutic modality. This Perspective discusses opportunities and challenges for expanding the applicability of targeted protein degradation, with a focus on the large family of E3 ubiquitin ligases that have a key role in the process.

    • Matthieu Schapira
    • Matthew F. Calabrese
    • Craig M. Crews
  • Adaptive platform trials, which can study multiple therapeutic interventions in a disease in a perpetual manner, offer the potential to improve the efficiency of drug development. This article reviews common features and issues that arise with such trials, and puts forward recommendations to promote best practices in their design, conduct, oversight and reporting.

    • Derek C. Angus
    • Brian M. Alexander
    • Janet Woodcock
  • Adhesion G protein-coupled receptors (aGPCRs) have been linked to multiple diseases, but no therapeutics targeting this GPCR family are yet in clinical trials, in part because a lack of understanding of the atypical features of aGPCRs has hampered the development of molecules targeting them. In this Perspective, Bassilana and colleagues discuss how recent advances in aGPCR biology could provide the basis for a framework to approach the unique challenges of drug discovery programmes targeting these receptors.

    • Frederic Bassilana
    • Mark Nash
    • Marie-Gabrielle Ludwig
  • Cells in the innate immune system can display adaptive characteristics that lead to increased responsiveness to secondary stimulation by pathogens. This innate immune memory has been termed ‘trained immunity’. Here, Mulder and colleagues describe the mechanisms responsible for the induction of trained immunity and propose strategies to regulate it as a potential treatment of immune-related diseases.

    • Willem J. M. Mulder
    • Jordi Ochando
    • Mihai G. Netea
  • In 2014, the Illuminating the Druggable Genome programme was launched to promote the exploration of currently understudied but potentially druggable proteins. This article discusses how the systematic collection and processing of a wide array of biological and chemical data as part of this programme has enabled the development of evidence-based criteria for tracking the target development level of human proteins, which indicates a substantial knowledge deficit for approximately one out of three proteins in the human proteome. It also highlights the nature of the unexplored therapeutic opportunities for major protein families.

    • Tudor I. Oprea
    • Cristian G. Bologa
    • Gergely Zahoránszky-Köhalmi
  • Shih and colleagues analyse comprehensive industry-wide data on drug development projects pursued during the past 20 years, classified according to the mechanism and indication for each project. Their findings indicate several points and trends that may be useful in understanding and improving the productivity of the pharmaceutical industry, including areas with substantial success or failure and the relative extent of novelty in completed and ongoing projects.

    • Hsin-Pei Shih
    • Xiaodan Zhang
    • Alex M. Aronov
  • G protein-coupled receptors (GPCRs) are the most intensively studied class of drug targets. This article presents a pioneering analysis of all GPCR-targeted drugs and agents that are currently in clinical trials, and discusses the trends across molecule types, drug targets and therapeutic indications.

    • Alexander S. Hauser
    • Misty M. Attwood
    • David E. Gloriam
  • The success of mechanism-based drug discovery depends on the definition of the drug target, but targets are often poorly defined in the literature. Here, Overington and colleagues present a comprehensive map of the molecular targets of approved drugs, and explore aspects including the footprint of target classes across disease areas, the success of privileged target families and drug target orthologues across standard model organisms.

    • Rita Santos
    • Oleg Ursu
    • John P. Overington
  • Attempts to reduce the number of efficacy- and safety-related failures that may be linked to the physicochemical properties of small-molecule drug candidates have been inconclusive owing to the limited size of data sets from individual companies. Waring and colleagues analyse the largest data set compiled so far on the causes of attrition for oral, small-molecule drug candidates, derived from a pioneering data-sharing effort by AstraZeneca, Eli Lilly and Company, GlaxoSmithKline and Pfizer.

    • Michael J. Waring
    • John Arrowsmith
    • Alex Weir
  • Previous analyses of new drug approvals have suggested that phenotypic screening strategies have been more productive than target-based approaches in the discovery of first-in-class small-molecule drugs. Eder and colleagues analysed the origins of the first-in-class drugs approved by the US Food and Drug Administration from 1999 to 2013, and found that target-based approaches have had a substantial impact in more recent years. They discuss the implications for drug discovery strategies, including viewing phenotypic screening as a novel discipline rather than as a neoclassical approach.

    • Jörg Eder
    • Richard Sedrani
    • Christian Wiesmann
  • There has been a resurgence of interest in the use of phenotypic screens in drug discovery as an alternative to target-focused approaches. Moffat and colleagues investigated the contribution of phenotypic assays in oncology by analysing the origins of the new small-molecule cancer drugs approved by the US Food and Drug Administration over the past 15 years. They also discuss technical and biological advances that could empower phenotypic drug discovery in oncology by enabling the development of mechanistically informed phenotypic screens.

    • John G. Moffat
    • Joachim Rudolph
    • David Bailey
  • Ligand efficiency metrics quantify the molecular properties required to gain binding affinity for a drug target. This article discusses the application of such metrics in the selection and optimization of fragments, hits and leads, highlighting how optimizing ligand efficiency metrics based on both molecular mass and lipophilicity, when set in the context of the specific target, has the potential to increase the quality of drug candidates.

    • Andrew L. Hopkins
    • György M. Keserü
    • Charles H. Reynolds
  • Effectively selecting therapeutic targets from the sizeable lists that are emerging from large-scale multi-omics initiatives is a key challenge in drug discovery. This article describes an objective, systematic computational assessment of biological and chemical space that can be applied to any human gene set to prioritize targets for further evaluation, and demonstrates its use on a set of 479 cancer-associated genes to identify new opportunities for drug discovery and repurposing.

    • Mishal N. Patel
    • Mark D. Halling-Brown
    • Bissan Al-Lazikani