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Design of a truncated cardiotoxin-I analogue with potent insulinotropic activity

Nguyen, Thi Tuyet Nhung; Folch, Benjamin; Létourneau, Myriam; Truong, Nam Hai; Doucet, Nicolas; Fournier, Alain; Chatenet, David (2014). Design of a truncated cardiotoxin-I analogue with potent insulinotropic activity Journal of Medicinal Chemistry , vol. 57 , nº 6. p. 2623-33. DOI: 10.1021/jm401904q.

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Résumé

Insulin secretion by pancreatic beta-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 (Kv) and calcium-activated potassium channels (KCa). 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-I41-60 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 beta-cell physiology or even open a new therapeutic avenue for the treatment of type 2 diabetes.

Type de document: Article
Mots-clés libres: -
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 27 sept. 2017 18:31
Dernière modification: 27 sept. 2017 18:31
URI: http://espace.inrs.ca/id/eprint/3089

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