Disrupting GPCR complexes with smart drug-like peptides

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• dc.contributor.author Gallo, María, 1989-
• dc.contributor.author Defaus, Sira
• dc.contributor.author Andreu Martínez, David
• dc.date.accessioned 2022-02-16T07:41:29Z
• dc.date.available 2022-02-16T07:41:29Z
• dc.date.issued 2022
• dc.description.abstract G protein-coupled receptors (GPCRs) are a superfamily of proteins classically described as monomeric transmembrane (TM) receptors. However, increasing evidence indicates that many GPCRs form higher-order assemblies made up of monomers pertaining to identical (homo) or to various (hetero) receptors. The formation and structure of these oligomers, their physiological role and possible therapeutic applications raise a variety of issues that are currently being actively explored. In this context, synthetic peptides derived from TM domains stand out as powerful tools that can be predictably targeted to disrupt GPCR oligomers, especially at the interface level, eventually impairing their action. However, despite such potential, TM-derived, GPCR-disrupting peptides often suffer from inadequate pharmacokinetic properties, such as low bioavailability, a short half-life or rapid clearance, which put into question their therapeutic relevance and promise. In this review, we provide a comprehensive overview of GPCR complexes, with an emphasis on current studies using GPCR-disrupting peptides mimicking TM domains involved in multimerization, and we also highlight recent strategies used to achieve drug-like versions of such TM peptide candidates for therapeutic application.
• dc.description.sponsorship Financial support from the Spanish Ministry of Economy and Innovation (AGL2017-84097-C2-2-R, FEDER funds) and from La Caixa Banking Foundation (HR17-00409 and CI18-0045) is acknowledged.
• dc.format.mimetype application/pdf
• dc.identifier.citation Gallo M, Defaus S, Andreu D. Disrupting GPCR complexes with smart drug-like peptides. Pharmaceutics. 2022;14(1):161. DOI: 10.3390/pharmaceutics14010161
• dc.identifier.doi http://dx.doi.org/10.3390/pharmaceutics14010161
• dc.identifier.issn 1999-4923
• dc.identifier.uri http://hdl.handle.net/10230/52504
• dc.language.iso eng
• dc.publisher MDPI
• dc.relation.ispartof Pharmaceutics. 2022;14(1):161
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/AGL2017-84097-C2-2-R
• dc.rights © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri https://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword GPCR oligomers
• dc.subject.keyword Cyclic peptides
• dc.subject.keyword Non-natural amino acids
• dc.subject.keyword Peptide therapeutics
• dc.subject.keyword Retro-enantio
• dc.subject.keyword Transmembrane peptides
• dc.title Disrupting GPCR complexes with smart drug-like peptides
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion