title: Investigation of structure-activity relationships of Oxyntomodulin (Oxm) using Oxm analogs.
abstract: Oxyntomodulin (Oxm) is an intestinal peptide that inhibits food intake and body weight in rodents and humans. These studies used peptide analogs to study aspects of structure and function of Oxm, and the sensitivity of parts of the Oxm sequence to degradation. Analogs of Oxm were synthesized and studied using receptor binding and degradation studies in vitro. Their effects on food intake and conditioned taste avoidance were measured in vivo in rodents. Oxm breakdown by the enzyme dipeptidyl peptidase IV (DPPIV) was demonstrated in vitro and in vivo. In vitro degradation was reduced and in vivo bioactivity increased by inhibitors of DPPIV. Modifications to the N terminus of Oxm modulated binding to the glucagon-like peptide (GLP)-1 receptor and degradation by DPPIV. Modifications to the midsection of Oxm modulated binding to the GLP-1 receptor and degradation by neutral endopeptidase. These modifications also altered bioactivity in vivo. The C-terminal octapeptide of Oxm was shown to contribute to the properties of Oxm in vitro and in vivo but was not alone sufficient for the effects of the peptide. Elongation and acylation of the C terminus of Oxm altered GLP-1 receptor binding and duration of action in vivo, which may be due to changes in peptide clearance. An Oxm analog was developed with enhanced pharmaceutical characteristics, with greater potency and longevity with respect to effects on food intake. These studies suggest that Oxm is a potential target for antiobesity drug design.
authors.affiliation: Department of Investigative Medicine, Imperial College London, London, United Kingdom. s.bloom@imperial.ac.uk
authors.forename: Maralyn R
authors.initials: MR
authors.lastname: Druce
authors.forename: James S
authors.initials: JS
authors.lastname: Minnion
authors.forename: Benjamin C T
authors.initials: BC
authors.lastname: Field
authors.forename: Sejal R
authors.initials: SR
authors.lastname: Patel
authors.forename: Joyceline C
authors.initials: JC
authors.lastname: Shillito
authors.forename: Michael
authors.initials: M
authors.lastname: Tilby
authors.forename: Kylie E L
authors.initials: KE
authors.lastname: Beale
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Murphy
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Ghatei
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Bloom
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004435:Eating / Q000187:drug effects; D000067757:Glucagon-Like Peptide-1 Receptor; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D053772:Oxyntomodulin / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D018027:Receptors, Glucagon / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
chemical_list: C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D053772:Oxyntomodulin; D018027:Receptors, Glucagon