Rational Screening for Inhibitors of the HIV Integrase-Ku70 (XRCC6) Interaction

Ilgova, E.; Galkin, S.; Anisenko, A.; Gottikh, M.

Авторы: Ilgova Ekaterina, Galkin Simon, Anisenko Andrey, Gottikh Marina
Журнал: Protein Science
Том: 30
Номер: S1
Год издания: 2021
Издательство: Cold Spring Harbor Laboratory Press
Местоположение издательства: United States
Первая страница: 58
Последняя страница: 59
Аннотация: HIV epidemic largely affects economic growth and is likely to exacerbate income inequality and increase poverty. Current ways to fight the virus include prevention measures and usage of Highly Active Antiretroviral Therapy aimed to suppress viral replication. HIV has extremely high mutation rates, and resistant strains have been developed for almost every available drug. Consequently, there is a continuous demand to search for novel anti-HIV drugs that will be insensitive to the virus's high mutation rate. Targeting virus-host protein-protein interactions is a promising strategy to develop such drugs due to the genetic conservativeness of host proteins. A varietyof cellular proteins are needed for the successful integration of viral cDNA. Among them, Ku70/Ku80heterodimer facilitates post-integrational DNA repair. The interaction of IN and Ku70 has been shown. Disruption of the IN-Ku70 complex by point mutations at IN suppresses HIV replication. Therefore, the IN-Ku70 complex is a promising target for the development of novel anti-HIV drugs. Here we present a screening for inhibitorsof IN-Ku70 interaction. We have identified Ku70amino acids crucial for HIV integrase binding. These residues are part of a cavity suitable for molecular docking. At first, about 50,000 structurally diverse compounds from the ChemDiv vendor were submitted to the docking analysis. For the highest-ranking compounds, the solvent-accessible surface area of IN binding site withinKu70 was calculated. 31 compounds shielding IN interacting residues the most were selected for further biological evaluation. From 31 chosen molecules, two hit compounds moderately inhibited IN-Ku70 interaction (IC50 = 70-80 μM). These compounds provide a proof of concept that inhibition of IN-Ku70 interaction is possible.However, further structure optimization is needed to develop compounds with higher inhibitory activity. The work was supported by RFBR grant 18-29-08012.
Добавил в систему: Готтих Марина Борисовна

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