Open AccessOptimization of Truncated Glucagon Peptides to Achieve Selective, High Potency, Full Antagonists
Author(s) -
Bin Yang,
Vasily Gelfanov,
Diego Pérez-Tilve,
Barent DuBois,
Rebecca Rohlfs,
Jay J. Levy,
Jonathan D. Douros,
Brian Finan,
John P. Mayer,
Richard D. DiMarchi
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c02069
Subject(s) - glucagon , chemistry , antagonist , potency , ic50 , glucagon receptor , antagonism , receptor , in vivo , peptide , biological activity , pharmacology , glucagon like peptide 1 , biochemistry , in vitro , endocrinology , hormone , biology , diabetes mellitus , microbiology and biotechnology , type 2 diabetes
Antagonism of glucagon's biological action is a proven strategy for decreasing glucose in diabetic animals and patients. To achieve full, potent, and selective suppression, we chemically optimized N-terminally truncated glucagon fragments for the identification and establishment of the minimum sequence peptide, [Glu9]glucagon(6-29) amide ( 11 ) as a full antagonist in cellular signaling and receptor binding (IC 50 = 36 nM). Substitution of Phe6 with l-3-phenyllactic acid (Pla) produced [Pla6, Glu9]glucagon(6-29) amide ( 21 ), resulting in a 3-fold improvement in receptor binding (IC 50 = 12 nM) and enhanced antagonist potency. Further substitution of Glu9 and Asn28 with aspartic acid yielded [Pla6, Asp28]glucagon amide ( 26 ), which demonstrated a further increase in inhibitory potency (IC 50 = 9 nM), and improved aqueous solubility. Peptide 26 and a palmitoylated analogue, [Pla6, Lys10(γGluγGlu-C16), Asp28]glucagon(6-29) amide ( 31 ), displayed sustained duration in vivo action that successfully reversed glucagon-induced glucose elevation in mice.