Descripción del proyecto
Estrategia de «bloqueo y apoptosis» para combatir el VIH
El virus de la inmunodeficiencia humana (VIH) sigue constituyendo un grave problema de salud pública y, hasta el momento, se ha cobrado más de cuarenta millones de vidas. A pesar de las iniciativas por acabar con la epidemia de VIH/sida, todavía no ha sido posible erradicarlos. Recientemente se ha observado que, incluso tras el tratamiento, en el cuerpo permanece un depósito vírico que es demasiado resistente a los fármacos antirretrovíricos. El objetivo del proyecto Super-HIPPO, financiado por las Acciones Marie Skłodowska-Curie, es desarrollar una nueva estrategia denominada «bloqueo y apoptosis». Se basa en un derivado no natural de hexafosfato de inositol, L-HIPPO, que durante la prueba demostró producir un fuerte efecto sobre las células HeLa infectadas con VIH. El objetivo ahora es desarrollar un derivado de L-HIPPO nuevo más eficiente, que pueda administrarse por vía oral.
Objetivo
Main challenge of fighting with the HIV is to eliminate the latent viral reservoir from the body. This reservoir is resistant to antiretroviral drug therapy and can cause viral rebound if the treatment is stopped. The removal of the reservoir enables HIV eradication, is urgently desired in HIV-AIDS research. For this purpose, a strategy called “kick and kill” was proposed, based on the hypothesis that activation of latent HIV (“kick”) leads to cell death (“kill”) by physical damage and/or immune activation. However, in clinical tests “kill” process was found to be not enough to reach HIV eradication.
To eradicate HIV from the body, my work has recently suggested a new strategy called “lock-in and apoptosis” instead of “kick and kill”. In development of this strategy, non-natural derivative of inositol hexaphosphate (IP6) named as L-HIPPO was designed based on the fact that the MA domain of Pr55gag which mediates membrane binding through its interaction with inositol phospholipid PIP2 in the host membrane. L-HIPPO was administrated to HIV infected HeLa cells as complex with a carrier α-CDE and suppressed membrane localization of HIV-1 Gag protein and induced strong apoptosis of the host cell containing the latent viruses. In contrast, α-CDE-L-HIPPO induced less apoptosis on T cell line. Besides, the complex of α-CDE-L-HIPPO is inapplicable for oral use. Toward this end, new L-HIPPO derivative with alternative carrier is required.
An ultimate goal of this work is to develop new L-HIPPO derivative (Super-HIPPO) with more potent and efficient activities. My objectives to reach this goal are (1) to synthesize new L-HIPPO derivatives and alternative carriers, (2) to evaluate their activities, (3) to repeat design, synthesis and biological evaluation, if the activities are not enough, (4) to confirm the binding mode of MA-compound, and (5) to achieve personal development and career advancement by performing this study.
Ámbito científico
Programa(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Régimen de financiación
HORIZON-AG-UN - HORIZON Unit GrantCoordinador
35620 İzmir
Turquía