title: Data-driven synthesis of proteolysis-resistant peptide hormones.
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.
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University , Cambridge, Massachusetts 02138, United States.
authors.forename: Michaela
authors.initials: M
authors.lastname: Prothiwa
authors.forename: Ismail
authors.initials: I
authors.lastname: Syed
authors.forename: Mark O
authors.initials: MO
authors.lastname: Huising
authors.forename: Talitha
authors.initials: T
authors.lastname: van der Meulen
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Donaldson
authors.forename: Sunia A
authors.initials: SA
authors.lastname: Trauger
authors.forename: Barbara B
authors.initials: BB
authors.lastname: Kahn
authors.forename: Alan
authors.initials: A
authors.lastname: Saghatelian
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D060326:Chemistry Techniques, Synthetic; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D008969:Molecular Sequence Data; D036361:Peptide Hormones / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D059748:Proteolysis
chemical_list: D001786:Blood Glucose; D007328:Insulin; D036361:Peptide Hormones