Опубликовано: Идентификация новых низкомолекулярных ингибиторов сборки вирусных частиц HIV-1
Спустя 2 года после первоначальной попытки опубликовать работу по новым ингибиторам репликации вируса HIV-1 с новым механизмом действия, а именно ингибированием сборки матричного белка HIV MA/p17, наконец, удалось опубликовать работу в JBMC Letters. Эта работа первая в цикле (молекул найдено много), все молекулы новые, найденные при помощи молекулярного моделирования, и не имеют аналогов, ни структурных среди антивирусных молекул, ни функционально.
Identification of a small-molecule inhibitor of HIV-1 assembly that targets the phosphatidylinositol (4,5)-bisphosphate binding site of the HIV-1 matrix protein.
Isaac Zentner, Luz-Jeannette Sierra, Ayesha K. Fraser, Lina Maciunas, Marie K. Mankowski, Melanie B. Pallansch-Cokonis, Andrei Vinnik, Peter Fedichev, Roger G. Ptak, Julio Martín-García, and Simon Cocklin (Quantum, Drexel Medical College, SRI)
Owing to the emergence of drug-resistant strains and the cumulative toxicities associated with current therapies, demand remains for new inhibitors of HIV-1 replication. The HIV-1 MA protein, encoded as the N-terminal portion of Gag, is critically involved in the late, assembly stages in the life cycle of HIV-1. Firstly, HIV-1 MA is proposed to act as a scaffold that brings together Env and Gag proteins in infected cells. Several lines of evidence support an interaction of MA with the gp41 cytoplasmic tail during assembly and facilitating the incorporation of Env into virus particle. Until recently, this interaction was thought to be direct, however, other studies have implicated the participation of a cellular factor in both the interaction between Env and Gag and the process of envelope incorporation.
Тhe structure of the PI(4,5)P2 - MA complex has been solved by nuclear magnetic spectroscopy (NMR). The PI(4,5)P2 -binding site is resides in a cleft in the HIV-1 MA globular head domain and is composed of a large amount of charged residues. The majority of these residues are highly conserved across the HIV-1 subtypes, highlighting the functional importance of the PI(4,5)P2 - MA interaction in the HIV-1 replication cycle. Given its functional importance, and its high degree of conservation across isolates, we propose that the PI(4,5)P2-binding site may represent a new attractive antiviral target. Moreover, using a combination of virtual and surface plasmon resonance (SPR)-based screening we have previously identified a compound, N2-(Phenoxyacetyl)-N-[4-(1-piperidinylcarbonyl)benzyl]glycinamide (compound 14) , that interacts with HIV-1 MA in the PI(4,5)P2-binding site and displays broad range antiviral activity (Zentner et al., submitted). In this study, we performed further virtual screening to identify other compounds that could inhibit viral replication by disrupting the critical interaction of the MA protein with PI(4,5)P2. This approach resulted in the identification of a new compound (compound 7) that interacts with the MA protein, disrupts the interaction between MA and PI(4,5)P2, and possesses broad-spectrum anti-HIV-1 activity.
К сожалению, решение о публикации журнал принял через неделю после опубликования работы ближайших конкурентов, Два года бодания с рецензентами ушли на то, чтобы доказать, что ингибитор матричного протеина ВИЧ может быть и ингибитором входа. На уточнение механизма действия. Теперь есть и более активные молекулы, а работа продолжается в рамках Сколковского гранта. Завтра придут результаты исследований новых молекул, "держим пальцы"
Identification of a small-molecule inhibitor of HIV-1 assembly that targets the phosphatidylinositol (4,5)-bisphosphate binding site of the HIV-1 matrix protein.
Isaac Zentner, Luz-Jeannette Sierra, Ayesha K. Fraser, Lina Maciunas, Marie K. Mankowski, Melanie B. Pallansch-Cokonis, Andrei Vinnik, Peter Fedichev, Roger G. Ptak, Julio Martín-García, and Simon Cocklin (Quantum, Drexel Medical College, SRI)
Owing to the emergence of drug-resistant strains and the cumulative toxicities associated with current therapies, demand remains for new inhibitors of HIV-1 replication. The HIV-1 MA protein, encoded as the N-terminal portion of Gag, is critically involved in the late, assembly stages in the life cycle of HIV-1. Firstly, HIV-1 MA is proposed to act as a scaffold that brings together Env and Gag proteins in infected cells. Several lines of evidence support an interaction of MA with the gp41 cytoplasmic tail during assembly and facilitating the incorporation of Env into virus particle. Until recently, this interaction was thought to be direct, however, other studies have implicated the participation of a cellular factor in both the interaction between Env and Gag and the process of envelope incorporation.
Тhe structure of the PI(4,5)P2 - MA complex has been solved by nuclear magnetic spectroscopy (NMR). The PI(4,5)P2 -binding site is resides in a cleft in the HIV-1 MA globular head domain and is composed of a large amount of charged residues. The majority of these residues are highly conserved across the HIV-1 subtypes, highlighting the functional importance of the PI(4,5)P2 - MA interaction in the HIV-1 replication cycle. Given its functional importance, and its high degree of conservation across isolates, we propose that the PI(4,5)P2-binding site may represent a new attractive antiviral target. Moreover, using a combination of virtual and surface plasmon resonance (SPR)-based screening we have previously identified a compound, N2-(Phenoxyacetyl)-N-[4-(1-piperidinylcarbonyl)benzyl]glycinamide (compound 14) , that interacts with HIV-1 MA in the PI(4,5)P2-binding site and displays broad range antiviral activity (Zentner et al., submitted). In this study, we performed further virtual screening to identify other compounds that could inhibit viral replication by disrupting the critical interaction of the MA protein with PI(4,5)P2. This approach resulted in the identification of a new compound (compound 7) that interacts with the MA protein, disrupts the interaction between MA and PI(4,5)P2, and possesses broad-spectrum anti-HIV-1 activity.
К сожалению, решение о публикации журнал принял через неделю после опубликования работы ближайших конкурентов, Два года бодания с рецензентами ушли на то, чтобы доказать, что ингибитор матричного протеина ВИЧ может быть и ингибитором входа. На уточнение механизма действия. Теперь есть и более активные молекулы, а работа продолжается в рамках Сколковского гранта. Завтра придут результаты исследований новых молекул, "держим пальцы"