Design of potent and proteolytically stable double biaryl-stapled GLP-1R/GIPR peptide dual agonists.

Yifang Yang, Qing Lin

Abstract read

In one paragraph

Article in Bioorganic & medicinal chemistry, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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5 · Who and what money

Authors and funding

2 authors.

Yifang YangTransira Therapeutics, Baird Research Park, Amherst, New York 14228, United States.

Qing LinTransira Therapeutics, Baird Research Park, Amherst, New York 14228, United States; Department of Chemistry, State University of New York at Buffalo, Buffalo, New York 14260, United States. Electronic address: qinglin@buffalo.edu.

Funding

Development of Orally Administered Peptide Hormones for Treatment of Diabetes and ObesityR43DK130721 · NIDDK · TRANSIRA THERAPEUTICS, LLC · PI LIN, QING, YANG, YIFANG · 2021 to 2021

$300k

NIDDK NIH HHS R43 DK130721

6 · The paper itself

Abstract

The successful treatment of type 2 diabetes and obesity with tirzepatide highlights the dual agonists of glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic peptide receptor (GIPR) as a powerful new generation of anti-diabetic drugs. However, tirzepatide and other GLP-1R/GIPR dual agonists currently in clinical development are linear peptides susceptible to proteolytic cleavage, thus preventing their uses as oral drugs. Previously, we reported the design of the proteolytically stable GLP-1R/GIPR peptide dual agonists via sidechain biaryl stapling. Although the stapled peptides exhibit improved proteolytic stability, they are still not sufficiently stable for oral delivery. Here, we report on the design and synthesis of more stable GLP-1R/GIPR dual agonists through a combined use of double biaryl stapling and α-methylation. One of the double-stapled and α-methylated peptides, DA23-Bpy

Indexed as

Drug DesignGlucagon-Like Peptide-1 ReceptorGlucagon-Like Peptide-1 Receptor AgonistsHypoglycemic AgentsPeptidesReceptors, Gastrointestinal HormoneAnimalsDose-Response Relationship, DrugHumansMolecular StructureProteolysisRatsStructure-Activity Relationshipgastric inhibitory polypeptide receptorGlucagon-Like Peptide-1 ReceptorGlucagon-Like Peptide-1 Receptor AgonistsHypoglycemic AgentsPeptidesReceptors, Gastrointestinal HormoneDual agonistGlucagon-like peptide-1 receptor agonistGlucose-dependent insulinotropic peptide receptor agonistOral peptide drugsPeptide stapling

Identifiers

PMID40311601

DOI10.1016/j.bmc.2025.118215

PMCPMC13532390

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.