Data-Driven Synthesis of Proteolysis-Resistant Peptide Hormones

• Published in: Journal of the American Chemical Society Vol. 136; no. 51; pp. 17710 - 17713
• Main Authors: Prothiwa, Michaela, Syed, Ismail, Huising, Mark O, van der Meulen, Talitha, Donaldson, Cynthia J, Trauger, Sunia A, Kahn, Barbara B, Saghatelian, Alan
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 24.12.2014
• Subjects: Amino Acid Sequence; Animals; Blood Glucose - metabolism; Chemistry Techniques, Synthetic; Insulin - metabolism; Insulin Secretion; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Mass Spectrometry; Mice; Molecular Sequence Data; Peptide Hormones - chemical synthesis; Peptide Hormones - chemistry; Peptide Hormones - metabolism; Peptide Hormones - pharmacology; Proteolysis
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja5065735

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.