Discovery of a semi-synthesized cyclolignan as a potent HIV-1 non-nucleoside reverse transcriptase inhibitor

Abstract

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are essential components of highly active antiretroviral therapy (HAART) for human immunodeficiency virus type 1 (HIV-1) infection. In this study, we identified (+)-(7′S,8S,8’S)-3′,4,4′,5,5′-pentamethoxy-2,7′-cyclolignan (SG-1), a cyclolignan semi-synthesized from Machilus robusta and M. wangchiana extracts, as a potent NNRTI. SG-1 displayed anti-HIV-1 activity with an IC₅₀ of 0.77 μmol/L by inhibiting reverse transcriptase (RT) RNA-dependent DNA polymerase activity through a direct binding. It had synergistic effects when combined with tenofovir/lamivudine or zidovudine/lamivudine. The pharmacodynamics properties of SG-1 render it a valuable lead for the development of novel NNRTIs.

Keywords:

• Cyclolignan
• HIV-1
• non-nucleoside reverse transcriptase inhibitor
• drug resistance
• drug combinations