Chronic health conditions such as type II diabetes, obesity, Alzheimer’s disease, and Parkinson’s disease have potential to be treated by a single gut hormone, glucagon-like peptide-1 (GLP-1). GLP-1 binds to and activates its cognate G protein-coupled receptor (GPCR), GLP-1R, to stimulate secretion of insulin in a glucose dependent manner and has been shown to display neuroprotective effects. Unfortunately, when GLP-1 is in systemic circulation, it is inactivated within ~90 seconds by the serine protease, dipeptidyl peptidase-IV (DPP-IV). Enzymatic hydrolysis by DPP-IV results in removal of the two N-terminal amino acids, His-Ala, resulting in a truncated peptide that is orders of magnitude less potent. Common strategies to circumvent enzymatic degradation and delay renal clearance include mutation of the second N-terminal amino acid, alanine, to aminoisobutyric acid and/or lipidation at Lys26 to facilitate binding to serum albumin. Unfortunately, all clinically successful GLP-1 analogues are still susceptible to DPP-IV proteolysis or require administration by subcutaneous injection. We describe here efforts to (1) prevent DPP-IV degradation of GLP-1 by altering the pKa, polarity, or steric bulk of the N-terminal amine and (2) increase oral uptake of protease stable peptides by the addition of side chains to facilitate barrier transport all while still retaining receptor potency and efficacy. These chemical modifications will be achieved through alkylation by reductive amination or fluorination with a trivalent iodonium salt. We present here several GLP-1 analogues obtained through chemical design that have extended half-lives in vivo and promise for delivering the next generation of orally administered peptide therapeutics.

Molecular design of roteolytically stable peptide based therapeutics

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.