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

J Asian Nat Prod Res. 2019 Jan;21(1):76-85. doi: 10.1080/10286020.2017.1417266. Epub 2017 Dec 27.

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; drug combinations; drug resistance; non-nucleoside reverse transcriptase inhibitor.

MeSH terms

  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / pharmacology*
  • Drug Discovery
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • Lignans / chemical synthesis
  • Lignans / pharmacology*
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / pharmacology*

Substances

  • Anti-HIV Agents
  • Lignans
  • Reverse Transcriptase Inhibitors
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase