Advances in therapeutic peptides targeting G protein-coupled receptors

AP Davenport, CCG Scully, C de Graaf… - Nature Reviews Drug …, 2020 - nature.com
AP Davenport, CCG Scully, C de Graaf, AJH Brown, JJ Maguire
Nature Reviews Drug Discovery, 2020nature.com
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 …
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.
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