Antiretroviral therapy (ART) can effectively suppress human immunodeficiency virus type 1 (HIV-1) replication and limit the disease progression. However, ART is unable to eradicate the virus, and the requirement for lifelong treatment may have side effects and poses a risk of the development of resistance. New approaches to prevent and treat HIV-1 infection should therefore be developed. HIV-1 capsid (CA) protein is an unexploited but attractive target for antiviral drug development. The hydrophobic cavity of C-terminal domain of CA (CA CTD) has been validated as a potential target for antiviral drugs. Binding of compounds to this conserved nonpolar groove in CA CTD allosterically disrupts the CA assembly. In the study described here, we screened 2,080 natural products to identify potential antiviral agents for further development to combat HIV-1 infection. From the primary screen at a fixed concentration of 50 µM, 16 compounds were found to be effective against this target. Then, 6 compounds observed in the primary screen were confirmed in dose-response experiments. Finally, the 6 selected compounds were tested against HIV-1-induced cytopathic effects. Two compounds showed inhibitory effect on HIV-1 replication, and the most active one, rubranol, inhibited viral replication at a moderate micromolar concentration (EC = 15.85 μM). The binding mode of rubranol and hirsutanonol to CA CTD were analyzed by molecular docking respectively, providing insight for design of drug targeting HIV-1 capsid. The research reports, for the first time, identification of natural products that showed potential as anti-HIV-1 agents by targeting conserved hydrophobic cavity of HIV-1 CA CTD.Copyright © 2020. Published by Elsevier B.V.
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