Peptide drugs have a range of favorable features such as superior efficacy, high selectivity and low toxicity, but suffer from their poor pharmacokinetics due to proteolytic instability and fast clearance. The late-stage functionalization of fully elaborated, drug-like peptides would be ideal to speed up the drug discovery process. Current chemistry toolbox for peptide late-stage functionalization (LSF) is very limited, especially for both chemo- and regioselective modifications. We investigated a mild, tryptophan C2-selective functionalization method for native peptides, including glucagon, GLP-1, oxyntomodulin (OXM), parathyroid hormone (PTH), etc. This novel transformation offers an orthogonal synthetic handle, which can be coupled with a fatty acid lipid to enhance the physicochemical, pharmacological and even biological properties of peptides. As a proof-of-concept, we showcased that the lipidation of glucagon peptide can substantially extend in vivo half-life from &lt; 5 min to 7 hours in rats.

Improving peptide pharmacokinetics through tryptophan late-stage lipidation

256th National Meeting (2018)

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