Advances in therapeutic peptides targeting G protein-coupled receptors

• Published in: Nature reviews. Drug discovery Vol. 19; no. 6; pp. 389 - 413
• Main Authors: Davenport, Anthony P., Scully, Conor C. G., de Graaf, Chris, Brown, Alastair J. H., Maguire, Janet J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2020; Nature Publishing Group
• Subjects: 631/154/51; 631/154/51/2313; 631/45/611; 692/699; Animals; Biomedical and Life Sciences; Biomedicine; Biotechnology; Cancer Research; Clinical Trials as Topic; Drug approval; Drug Design; Drug Evaluation, Preclinical; G proteins; Health aspects; Homeopathy; Humans; Ligands; Materia medica and therapeutics; Medicinal Chemistry; Molecular Medicine; Molecular Targeted Therapy; Pentagastrin; Peptide Library; Peptides; Peptides - pharmacokinetics; Peptides - pharmacology; Peptides - therapeutic use; Pharmacodynamics; Pharmacology/Toxicology; Protein Binding; Proteins; Receptors, G-Protein-Coupled - metabolism; Review Article; Signal Transduction; Therapeutics; Type 2 diabetes
• ISSN: 1474-1776; 1474-1784
• DOI: 10.1038/s41573-020-0062-z

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.