title: Glucose and weight control in mice with a designed ghrelin O-acyltransferase inhibitor.
abstract: Ghrelin is a gastric peptide hormone that stimulates weight gain in vertebrates. The biological activities of ghrelin require octanoylation of the peptide on Ser(3), an unusual posttranslational modification that is catalyzed by the enzyme ghrelin O-acyltransferase (GOAT). Here, we describe the design, synthesis, and characterization of GO-CoA-Tat, a peptide-based bisubstrate analog that antagonizes GOAT. GO-CoA-Tat potently inhibits GOAT in vitro, in cultured cells, and in mice. Intraperitoneal administration of GO-CoA-Tat improves glucose tolerance and reduces weight gain in wild-type mice but not in ghrelin-deficient mice, supporting the concept that its beneficial metabolic effects are due specifically to GOAT inhibition. In addition to serving as a research tool for mapping ghrelin actions, GO-CoA-Tat may help pave the way for clinical targeting of GOAT in metabolic diseases.
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Brad P
authors.initials: BP
authors.lastname: Barnett
authors.forename: Yousang
authors.initials: Y
authors.lastname: Hwang
authors.forename: Martin S
authors.initials: MS
authors.lastname: Taylor
authors.forename: Henriette
authors.initials: H
authors.lastname: Kirchner
authors.forename: Paul T
authors.initials: PT
authors.lastname: Pfluger
authors.forename: Vincent
authors.initials: V
authors.lastname: Bernard
authors.forename: Yu-yi
authors.initials: YY
authors.lastname: Lin
authors.forename: Erin M
authors.initials: EM
authors.lastname: Bowers
authors.forename: Chandrani
authors.initials: C
authors.lastname: Mukherjee
authors.forename: Woo-Jin
authors.initials: WJ
authors.lastname: Song
authors.forename: Patti A
authors.initials: PA
authors.lastname: Longo
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Leahy
authors.forename: Mehboob A
authors.initials: MA
authors.lastname: Hussain
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
authors.forename: Jef D
authors.initials: JD
authors.lastname: Boeke
authors.forename: Philip A
authors.initials: PA
authors.lastname: Cole
mesh_terms: D000215:Acylation; D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D054439:Ghrelin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D000071246:Uncoupling Protein 2; D015430:Weight Gain / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; C554860:GO-CoA-Tat; D054439:Ghrelin; D007328:Insulin; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D010455:Peptides; D000071246:Uncoupling Protein 2; D000217:Acyltransferases; C526983:Mboat4 protein, mouse; D005947:Glucose