A systematic structure-activity and computational modeling analysis of a series of glucagon-like peptide-1 receptor (GLP-1R) agonists based upon an ultra-short GLP-1 peptide, H-His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Bip-Bip-NH2, was conducted. This highly potent 11-mer peptide led to a deeper understanding of the α-helical bias of strategic α-methylation within the linear parent template as well as optimization of GLP-1R agonist potency by 1000-fold. These data were correlated with previously reported co-structures of both full-length GLP-1 analogs and progenitor N-terminal GLP-1 fragment analogs related to such ultra-short GLP-1R agonist peptides. Furthermore, the development of a quantitative structure-activity relationship (QSAR) model to analyze these findings is described in this study.
Keywords: 2-amino-isobutyric acid (Aib); Cα-methylation; glucagon-like peptide-1 (GLP-1); p-phenyl-phenylalanine (Bip); quantitative structure–activity relationship (QSAR); structure-based design; structure–activity relationship (SAR); α-methyl-phenylalanine (α-MePhe); α-methyl-phenylalanine [2-F] (α-MePhe[2-F]).