title: Design of Potent and Proteolytically Stable Oxyntomodulin Analogs.
abstract: Incretin-based peptides are effective therapeutics for treating type 2 diabetes mellitus (T2DM). Oxyntomodulin (OXM), a dual agonist of GLP-1R and GCGR, has shown superior weight loss and glucose lowering effects, compared to single GLP-1R agonists. To overcome the short half-life and rapid renal clearance of OXM, which limit its therapeutic potential, both lipid and PEG modified OXM analogs have been reported. However, these approaches often result in reduced potency or PEG-associated toxicity. Herein, we report a new class of cross-linked OXM analogs that show increased plasma stability and higher potency in activating both GLP-1R and GCGR. Moreover, the extended in vivo half-life results in superior antihyperglycemic activity in mice compared to the wild-type OXM.
authors.affiliation: California Institute for Biomedical Research (Calibr) , 11119 North Torrey Pines Road, La Jolla, California 92037, United States.|Department of Chemistry, State University of New York at Buffalo , Buffalo, New York 14260-3000, United States.
authors.forename: Avinash
authors.initials: A
authors.lastname: Muppidi
authors.affiliation: California Institute for Biomedical Research (Calibr) , 11119 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Huafei
authors.initials: H
authors.lastname: Zou
authors.affiliation: Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Peng Yu
authors.initials: PY
authors.lastname: Yang
authors.affiliation: California Institute for Biomedical Research (Calibr) , 11119 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Chao
authors.affiliation: California Institute for Biomedical Research (Calibr) , 11119 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Lance
authors.initials: L
authors.lastname: Sherwood
authors.affiliation: California Institute for Biomedical Research (Calibr) , 11119 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Nunez
authors.affiliation: California Institute for Biomedical Research (Calibr) , 11119 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Ashley K
authors.initials: AK
authors.lastname: Woods
authors.affiliation: California Institute for Biomedical Research (Calibr) , 11119 North Torrey Pines Road, La Jolla, California 92037, United States.|Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
authors.affiliation: Department of Chemistry, State University of New York at Buffalo , Buffalo, New York 14260-3000, United States.
authors.forename: Qing
authors.initials: Q
authors.lastname: Lin
authors.affiliation: California Institute for Biomedical Research (Calibr) , 11119 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Weijun
authors.initials: W
authors.lastname: Shen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003432:Cross-Linking Reagents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D053772:Oxyntomodulin / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology*; D059748:Proteolysis; D018027:Receptors, Glucagon / Q000819:agonists* / Q000378:metabolism; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D003432:Cross-Linking Reagents; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D053772:Oxyntomodulin; D018027:Receptors, Glucagon; D000097789:Glucagon-Like Peptide-1 Receptor Agonists