Data-driven synthesis of proteolysis-resistant peptide hormones

Michaela Prothiwa, Ismail Syed, Mark O. Huising, Talitha Van Der Meulen, Cynthia J. Donaldson, Sunia A. Trauger, Barbara B. Kahn, Alan Saghatelian

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Peptide hormones are key physiological regulators, and many would make terrific drugs; however, the therapeutic use of peptides is limited by poor metabolism including rapid proteolysis. To develop novel proteolysis-resistant peptide hormone analogs, we utilize a strategy that relies on data from simple mass spectrometry experiments to guide the chemical synthesis of proteolysis-resistant analogs (i.e., data-driven synthesis). Application of this strategy to oxyntomodulin (OXM), a peptide hormone that stimulates insulin secretion from islets and lowers blood glucose in vivo, defined the OXM cleavage site in serum, and this information was used to synthesize a proteolysis-resistant OXM analog (prOXM). prOXM and OXM have similar activity in binding and glucose stimulated-insulin secretion assays. Furthermore, prOXM is also active in vivo. prOXM reduces basal glucose levels and improves glucose tolerance in mice. The discovery of prOXM suggests that proteolysis-resistant variants of other important peptide hormones can also be found using this strategy to increase the number of candidate therapeutic peptides.

Original languageEnglish (US)
Pages (from-to)17710-17713
Number of pages4
JournalJournal of the American Chemical Society
Volume136
Issue number51
DOIs
StatePublished - Dec 24 2014
Externally publishedYes

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Fingerprint

Dive into the research topics of 'Data-driven synthesis of proteolysis-resistant peptide hormones'. Together they form a unique fingerprint.

Cite this