RESUMEN
Insulin secretion by pancreatic ß-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 ß-cell physiology or even open a new therapeutic avenue for the treatment of type 2 diabetes.
Asunto(s)
Proteínas Cardiotóxicas de Elápidos/síntesis química , Proteínas Cardiotóxicas de Elápidos/farmacología , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacología , Insulina/metabolismo , Animales , Calcio/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Diseño de Fármacos , Venenos Elapídicos/química , Glucosa/farmacología , Secreción de Insulina , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Modelos Moleculares , Conformación Molecular , Péptidos/síntesis química , Péptidos/farmacología , Bloqueadores de los Canales de Potasio/síntesis química , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio Calcio-Activados/efectos de los fármacos , Canales de Potasio con Entrada de Voltaje/efectos de los fármacos , Ratas , Rubidio/metabolismo , Radioisótopos de Rubidio , Estimulación QuímicaRESUMEN
L1AD3 is a small cyclic synthetic peptide designed to resemble the first loop of a cobra venom cytotoxin. Instead of inducing membrane disruption similar to that caused by the parent toxin, L1AD3 promotes extensive and unusually rapid apoptosis in leukemic T-cells without making the plasma membrane permeable to small fluorescent dyes. Within 4 h, micromolar concentrations of L1AD3 almost totally inhibit thymidine incorporation, and ATP levels decrease significantly. By contrast, normal human white blood cells are not affected by L1AD3, nor is heart cell function affected by it. If L1AD3 kills by interacting with targets that are different from those of currently applied agents, this peptide, or a derivative of it, could become a useful adjunct for cancer chemotherapy.