Advances in therapeutic peptides targeting G protein-coupled receptors
Anthony P. Davenport,Conor C. G. Scully,Chris de Graaf,Alastair J. H. Brown,Janet J. Maguire +4 more
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TLDR
A review of peptide drugs targeting G protein-coupled receptors (GPCRs) is presented in this paper, with a focus on evolving strategies to improve pharmacokinetic and pharmacodynamic properties.Abstract:
Dysregulation of peptide-activated pathways causes a range of diseases, fostering the discovery and clinical development of peptide drugs. Many endogenous peptides activate G protein-coupled receptors (GPCRs) — nearly 50 GPCR peptide drugs have been approved to date, most of them for metabolic disease or oncology, and more than 10 potentially first-in-class peptide therapeutics are in the pipeline. The majority of existing peptide therapeutics are agonists, which reflects the currently dominant strategy of modifying the endogenous peptide sequence of ligands for peptide-binding GPCRs. Increasingly, novel strategies are being employed to develop both agonists and antagonists, to both introduce chemical novelty and improve drug-like properties. Pharmacodynamic improvements are evolving to allow biasing ligands to activate specific downstream signalling pathways, in order to optimize efficacy and reduce side effects. In pharmacokinetics, modifications that increase plasma half-life have been revolutionary. Here, we discuss the current status of the peptide drugs targeting GPCRs, with a focus on evolving strategies to improve pharmacokinetic and pharmacodynamic properties. Many G protein-coupled receptors (GPCRs) have endogenous peptide agonists, and modifying the sequence of these peptides has led to some successful therapeutics. In this Review, Davenport and colleagues discuss strategies to generate effective GPCR-targeted peptide therapeutics by introducing chemical novelty, extending plasma half-life, improving a therapeutic’s drug-like properties or generating biased ligands. These approaches could overcome some of the challenges in developing peptide therapeutics.read more
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G protein-coupled receptors: structure- and function-based drug discovery.
Dehua Yang,Qingtong Zhou,Viktorija Labroska,Shanshan Qin,Sanaz Darbalaei,Yiran Wu,Elita Yuliantie,Linshan Xie,Houchao Tao,Jianjun Cheng,Qing Liu,Suwen Zhao,Wenqing Shui,Yi Jiang,Ming-Wei Wang +14 more
TL;DR: A comprehensive overview of the field of G protein-coupled receptors (GPCRs) can be found in this article, where the authors provide a broader readership that shares some common interests in drug discovery.
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Targeting Cannabinoid Receptors: Current Status and Prospects of Natural Products.
TL;DR: It is expected that more novel cannabinoids will be discovered and forecasted as promising drug leads from diverse natural sources and species, such as animal venoms which constitute a true pharmacopeia of toxins modulating diverse targets, with astonishing affinity and selectivity.
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Trends in peptide drug discovery
TL;DR: The early efforts focused on human hormones, elegant medicinal chemistry and rational design strategies, peptide drugs derived from nature, and major breakthroughs in molecular biology and peptide chemistry continue to advance the field as mentioned in this paper.
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A rational roadmap for SARS-CoV-2/COVID-19 pharmacotherapeutic research and development: IUPHAR Review 29.
Stephen P.H. Alexander,Jane F. Armstrong,Anthony P. Davenport,Jamie A. Davies,Elena Faccenda,Simon D. Harding,Francesca Levi-Schaffer,Janet J. Maguire,Adam J. Pawson,Christopher Southan,Michael Spedding +10 more
TL;DR: This review identifies opportunities for drug discovery in the treatment of COVID‐19 and provides a rational roadmap whereby pharmacology and pharmacologists can mitigate against the global pandemic.
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