title: Design of a truncated cardiotoxin-I analogue with potent insulinotropic activity.
abstract: Insulin secretion by pancreatic β-cells in response to glucose or other secretagogues is tightly coupled to membrane potential. Various studies have highlighted the prospect of enhancing insulin secretion in a glucose-dependent manner by blocking voltage-gated potassium channels (K(v)) and calcium-activated potassium channels (K(Ca)). Such strategy is expected to present a lower risk for hypoglycemic events compared to KATP channel blockers. Our group recently reported the discovery of a new insulinotropic agent, cardiotoxin-I (CTX-I), from the Naja kaouthia snake venom. In the present study, we report the design and synthesis of [Lys(52)]CTX-I(41-60) via structure-guided modification, a truncated, equipotent analogue of CTX-I, and demonstrate, using various pharmacological inhibitors, that this derivative probably exerts its action through Kv channels. This new analogue could represent a useful pharmacological tool to study β-cell physiology or even open a new therapeutic avenue for the treatment of type 2 diabetes.
authors.affiliation: INRS-Institut Armand-Frappier , Université du Québec , 531 Boulevard des Prairies Ville de Laval, Québec H7 V 1B7, Québec Canada.
authors.forename: Thi Tuyet Nhung
authors.initials: TT
authors.lastname: Nguyen
authors.forename: Benjamin
authors.initials: B
authors.lastname: Folch
authors.forename: Myriam
authors.initials: M
authors.lastname: Létourneau
authors.forename: Nam Hai
authors.initials: NH
authors.lastname: Truong
authors.forename: Nicolas
authors.initials: N
authors.lastname: Doucet
authors.forename: Alain
authors.initials: A
authors.lastname: Fournier
authors.forename: David
authors.initials: D
authors.lastname: Chatenet
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004179:Cobra Cardiotoxin Proteins / Q000138:chemical synthesis* / Q000494:pharmacology*; D015195:Drug Design; D004546:Elapid Venoms / Q000737:chemistry; D005947:Glucose / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000138:chemical synthesis / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000187:drug effects; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects; D051381:Rats; D012413:Rubidium / Q000378:metabolism; D012414:Rubidium Radioisotopes; D013268:Stimulation, Chemical
chemical_list: D004179:Cobra Cardiotoxin Proteins; D004546:Elapid Venoms; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D024642:Potassium Channels, Voltage-Gated; D012414:Rubidium Radioisotopes; D005947:Glucose; D012413:Rubidium; D002118:Calcium