Premium
Impact of Substitution Registry on the Receptor‐Activation Profiles of Backbone‐Modified Glucagon‐like Peptide‐1 Analogues
Author(s) -
Cary Brian P.,
Hager Marlies V.,
Gellman Samuel H.
Publication year - 2019
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201900300
Subject(s) - substitution (logic) , peptide , chemistry , receptor , glucagon like peptide 1 , combinatorial chemistry , glucagon , stereochemistry , biochemistry , biology , endocrinology , computer science , hormone , diabetes mellitus , type 2 diabetes , programming language
Family B G protein‐coupled receptors play important physiological roles and possess large extracellular domains (ECDs) that aid in binding the long polypeptide hormones that are their natural agonists. We have previously shown that agonist analogues in which subsets of native α‐amino acid residues are replaced with β‐amino acid residues can retain activity while avoiding proteolytic degradation. This study focuses on eight new α/β analogues of glucagon‐like peptide 1 (GLP‐1) that each contain five α‐to‐β replacements in the C‐terminal half of the peptide. This portion of GLP‐1 is known to adopt an α‐helical conformation and contact the ECD. All four registries of the αααβ backbone pattern were evaluated; previous work has shown that the αααβ pattern supports adoption of an α‐helix‐like conformation. Two α‐to‐β replacement formats were employed, one involving β 3 homologues of the native residues replaced and the other involving a cyclic β residue. GLP‐1R response was characterized in terms of stimulation of cAMP production and β‐arrestin recruitment. Some of the backbone‐modified GLP‐1 analogues display biased agonism of the GLP‐1R. This study helps to establish the scope of the α→β backbone modification strategy.