Natural-product-library-based screening for discovery of capsid C-terminal domain targeted HIV-1 inhibitors.

• HIV-1 capsid represents an unexploited but attractive target for antiviral drug development. • Two linear diarylheptanoids, identified as hits in the homogeneous time-resolved fluorescence assay, inhibited HIV-1 replication in cell culture. • For the first time, natural products were identified as anti-HIV-1 agents by targeting the conserved hydrophobic cavity of the HIV-1 capsid C-terminal domain. Antiretroviral therapy (ART) can effectively suppress replication of human immunodeficiency virus type 1 (HIV-1) and limit disease progression. However, ART is unable to eradicate the virus, and the requirement for lifelong treatment may have side effects and may lead to 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 the C-terminal domain of CA (CA CTD) has been validated as a potential target for antiviral drugs. Binding of compounds to this conserved non-polar groove in CA CTD allosterically disrupts the CA assembly. This study screened 2080 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. Six compounds observed in the primary screen were confirmed in dose–response experiments, and were tested against HIV-1-induced cytopathic effects. Two compounds were found to inhibit HIV-1 replication, and the most active compound – rubranol – inhibited viral replication at a moderate micromolar concentration (EC 50 = 15.85 μM). The binding modes of rubranol and hirsutanonol to CA CTD were analysed by molecular docking, providing insight for the design of drugs targeting HIV-1 CA. This study reports, for the first time, identification of natural products that showed potential as anti-HIV-1 agents by targeting the conserved hydrophobic cavity of HIV-1 CA CTD. [ABSTRACT FROM AUTHOR]