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Development of artificial phosphoinositides aiming at HIV eradication

Descrizione del progetto

Una strategia «kick and kill» per la cura dell’HIV

Il virus dell’immunodeficienza umana (HIV) non equivale più a una sentenza di morte. Una strategia di cura consiste nella rimozione dei serbatoi virali dal corpo, che consente di eliminare l’HIV dato che il serbatoio è resistente alla terapia farmacologica antiretrovirale. È stata proposta la cosiddetta strategia «kick and kill» (letteralmente, «calcio e uccisione») basata sull’ipotesi secondo cui l’attivazione dell’HIV latente (calcio) conduca alla morte cellulare (uccisione) attraverso danni fisici e/o l’attivazione immune. Tuttavia, i test clinici dimostrano che il processo di «uccisione» non è sufficiente a conseguire l’eliminazione dell’HIV. Il progetto Super-HIPPO, finanziato dall’UE, analizzerà gli agenti invertitori di latenza in grado di eseguire il «calcio» concentrando l’attenzione sul composto L-HIPPO, sintetizzato di recente. Super-HIPPO svilupperà un nuovo derivato di L-HIPPO (Super-HIPPO) con attività ottimizzate.

Obiettivo

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.

Coordinatore

IZMIR KATIP CELEBI UNIVERSITESI
Contribution nette de l'UE
€ 148 478,40
Indirizzo
IZMIR KATIP CELEBI UNIVERSITESI HAVAALANI SOSESI C NO.33, D.2
35620 İzmir
Turchia

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Regione
Ege İzmir İzmir
Tipo di attività
Higher or Secondary Education Establishments
Collegamenti
Costo totale
Nessun dato