HEИндивидуална стипендия2023–2025

Super-HIPPO · Development of artificial phosphoinositides aiming at HIV eradication

„Хоризонт Европа“ — Действия „Мария Склодовска-Кюри“

Период: 2023-09-01 → 2025-10-31
Финансиране от ЕС: 148 478 €
Участници: 1
Схема: HORIZON-TMA-MSCA-PF-EF

Линиите свързват координатора с партньорите.

Накратко на български

Изработват се изкуствени молекули, които блокират сглобяването на HIV вируса в клетката и задействат нейната програмирана смърт. Това помага за елиминирането на инфектираните клетки, които остават скрити от имунната система и причиняват повторна инфекция след спиране на терапията.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Development of artificial phosphoinositides aiming at HIV eradication

Despite major advances in antiretroviral therapy, HIV remains incurable due to the persistence of latent viral reservoirs that evade immune clearance and reignite infection if treatment is stopped. Current eradication strategies, such as the widely explored “kick and kill” approach, have shown limited success because reactivated infected cells are not efficiently eliminated. There is therefore a critical unmet need for innovative therapeutic concepts that prevent viral rebound and selectively eliminate infected cells. The Super-HIPPO project addresses this challenge by developing a fundamentally new strategy termed “lock-in and apoptosis.” Instead of reactivating latent virus, this approach blocks HIV assembly at the host cell membrane and simultaneously triggers programmed cell death in infected cells. The strategy targets the matrix (MA) domain of the HIV-1 Gag polyprotein, a key component required for viral particle formation through its interaction with host cell phosphoinositides. Building on earlier proof-of-concept studies, the project aimed to design and optimize a novel artificial phosphoinositide derivative (Super-HIPPO) with enhanced biological activity and improved intracellular delivery. The overarching objective was to generate a new class of anti-HIV agents capable of suppressing virus production and promoting selective apoptosis of infected cells, thereby contributing to long-term HIV eradication efforts. At a broader level, the project supports EU priorities in global health, innovation in antiviral therapies, and preparedness against persistent and emerging infectious diseases. By combining medicinal chemistry, nanotechnology, molecular Biology, and structural biology, Super-HIPPO establishes a scalable pathway toward transformative HIV therapies with potential impact well beyond the lifetime of the project.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

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.

Оригинален текст от CORDIS (на английски).

Участници

IZMIR KATIP CELEBI UNIVERSITESI · IZMIRКоординаторТурция