Structural Overview of GLP-1 Analogs.

Authors

Wijnand J C van der Velden, Asta F Andresen, Mette M Rosenkilde

Published in

Biomedical journal. Pages 101037. Sep 11, 2026. Epub Sep 11, 2026.

Abstract

Glucagon-like peptide-1 (GLP-1) analogs exert potent metabolic effects through structural features that govern receptor engagement, signaling, and pharmacokinetics. Key structural determinants include N-terminal modifications that confer resistance to dipeptidyl peptidase-4 degradation, as well as C-terminal and backbone elements that stabilize peptide helicity and enhance GLP-1 receptor affinity. Lipidation and albumin-binding strategies prolong systemic exposure by increasing circulating half-life, forming the basis of long-acting agents such as liraglutide and semaglutide. Structural variation further modulates signaling bias between G protein pathways and β-arrestin recruitment, potentially influencing therapeutic efficacy. Emerging multi-receptor agonists extend these principles across incretin receptor families and are increasingly supported by computational approaches to peptide optimization. Collectively, these advances illustrate how rational design drives the development of next-generation incretin therapeutics. This review synthesizes current insights into structural determinants of GLP-1 analogs and highlights future directions in the field.

PMID:
42727920
Bibliographic data and abstract were imported from PubMed on 12 Sep 2026.

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