title: DPP-IV-resistant, long-acting oxyntomodulin derivatives.
abstract: Obesity is one of the major risk factors for type 2 diabetes, and the development of agents, that can simultaneously achieve glucose control and weight loss, is being actively pursued. Therapies based on peptide mimetics of the gut hormone glucagon-like peptide 1 (GLP-1) are rapidly gaining favor, due to their ability to increase insulin secretion in a strictly glucose-dependent manner, with little or no risk of hypoglycemia, and to their additional benefit of causing a modest, but durable weight loss. Oxyntomodulin (OXM), a 37-amino acid peptide hormone of the glucagon (GCG) family with dual agonistic activity on both the GLP-1 (GLP1R) and the GCG (GCGR) receptors, has been shown to reduce food intake and body weight in humans, with a lower incidence of treatment-associated nausea than GLP-1 mimetics. As for other peptide hormones, its clinical application is limited by the short circulatory half-life, a major component of which is cleavage by the enzyme dipeptidyl peptidase IV (DPP-IV). SAR studies on OXM, described herein, led to the identification of molecules resistant to DPP-IV degradation, with increased potency as compared to the natural hormone. Analogs derivatized with a cholesterol moiety display increased duration of action in vivo. Moreover, we identified a single substitution which can change the OXM pharmacological profile from a dual GLP1R/GCGR agonist to a selective GLP1R agonist. The latter finding enabled studies, described in detail in a separate study (Pocai A, Carrington PE, Adams JR, Wright M, Eiermann G, Zhu L, Du X, Petrov A, Lassman ME, Jiang G, Liu F, Miller C, Tota LM, Zhou G, Zhang X, Sountis MM, Santoprete A, Capitò E, Chicchi GG, Thornberry N, Bianchi E, Pessi A, Marsh DJ, SinhaRoy R. Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in mice. Diabetes 2009; 58: 2258-2266), which highlight the potential of GLP1R/GCGR dual agonists as a potentially superior class of therapeutics over the pure GLP1R agonists currently in clinical use.
authors.affiliation: Istituto di Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Santoprete
authors.forename: Elena
authors.initials: E
authors.lastname: Capitò
authors.forename: Paul E
authors.initials: PE
authors.lastname: Carrington
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pocai
authors.forename: Marco
authors.initials: M
authors.lastname: Finotto
authors.forename: Annunziata
authors.initials: A
authors.lastname: Langella
authors.forename: Paolo
authors.initials: P
authors.lastname: Ingallinella
authors.forename: Karolina
authors.initials: K
authors.lastname: Zytko
authors.forename: Simone
authors.initials: S
authors.lastname: Bufali
authors.forename: Simona
authors.initials: S
authors.lastname: Cianetti
authors.forename: Maria
authors.initials: M
authors.lastname: Veneziano
authors.forename: Fabio
authors.initials: F
authors.lastname: Bonelli
authors.forename: Lan
authors.initials: L
authors.lastname: Zhu
authors.forename: Edith
authors.initials: E
authors.lastname: Monteagudo
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Marsh
authors.forename: Ranabir
authors.initials: R
authors.lastname: Sinharoy
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bianchi
authors.forename: Antonello
authors.initials: A
authors.lastname: Pessi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D004435:Eating / Q000187:drug effects; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009765:Obesity / Q000188:drug therapy; D053772:Oxyntomodulin / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000235:genetics; D015431:Weight Loss / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D053772:Oxyntomodulin; D010455:Peptides; D018819:Dipeptidyl Peptidase 4