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.

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“…ShK-186 selectively blocks the Kv1.3 channel that has been implicated in the regulation of energy homeostasis and body weight [20]. Snake venom also contains lots of potassium channels blockers [21–23]. ShK-186 significantly reduced weight gain, fat accumulation, and associated inflammation in diet-induced obese mice [24].…”

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“… 153 Thus, it could be utilised to gain a better understanding of the important Kv channel-dependent insulin secretory pathway in pancreatic beta cells. 154 In addition, Moore et al isolated insulin releasing compounds from Crotalus adamanteus, Crotalus vegrandis and Bitis nasicornis snakes by gel filtration chromatography. The insulinotropic action appeared to be linked to serine proteinases, phospholipases A 2 (PLA 2 ) and disintegrins within the venom.…”

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“…In contrast to typical cobra cardiotoxin, CTX-I did not induce direct hemolysis of human erythrocytes and showed no potent vasoconstriction capability. Based upon this toxin, a truncated analogue [Lys(52)CTX-I(41-60)] was obtained by structure-guided modification[47]. This analogue showed insulinotropic activity similar to CTX-I and appeared to exert its action through K v channels[47].…”

“…Based upon this toxin, a truncated analogue [Lys(52)CTX-I(41-60)] was obtained by structure-guided modification[47]. This analogue showed insulinotropic activity similar to CTX-I and appeared to exert its action through K v channels[47]. As such, it may serve as a basis for the design of new therapeutic agents for the treatment of type 2 diabetes (Table 1).…”