F18, a novel small-molecule nonnucleoside reverse transcriptase inhibitor, inhibits HIV-1 replication using distinct binding motifs as demonstrated by resistance selection and docking analysis

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

19 Scopus Citations
View graph of relations

Author(s)

  • Xiaofan Lu
  • Li Liu
  • Xu Zhang
  • Stephen Kwok Wing Tsui
  • Yuanxi Kang
  • Purong Zheng
  • Bojian Zheng
  • Gang Liu
  • Zhiwei Chen

Detail(s)

Original languageEnglish
Pages (from-to)341-351
Journal / PublicationAntimicrobial Agents and Chemotherapy
Volume56
Issue number1
Publication statusPublished - Jan 2012

Abstract

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are one of the key components of antiretroviral therapy drug regimen against human immunodeficiency virus type 1 (HIV-1) replication. We previously described a newly synthesized small molecule, 10-chloromethyl-11-demethyl-12-oxo-calanolide A (F18), a (+)-calanolide A analog, as a novel anti-HIV-1 NNRTI (H. Xue et al., J. Med. Chem. 53:1397-1401, 2010). Here, we further investigated its antiviral range, drug resistance profile, and underlying mechanism of action. F18 consistently displayed potent activity against primary HIV-1 isolates, including various subtypes of group M, circulating recombinant form (CRF) 01-AE, and laboratory-adapted drug-resistant viruses. Moreover, F18 displayed distinct profiles against 17 NNRTI-resistant pseudoviruses, with an excellent potency especially against one of the most prevalent strains with the Y181C mutation (50% effective concentration, 1.0 nM), which was in stark contrast to the extensively used NNRTIs nevirapine and efavirenz. Moreover, we induced F18-resistant viruses by in vitro serial passages and found that the mutation L100I appeared to be the dominant contributor to F18 resistance, further suggesting a binding motif different from that of nevirapine and efavirenz. F18 was nonantagonistic when used in combination with other antiretrovirals against both wild-type and drug-resistant viruses in infected peripheral blood mononuclear cells. Interestingly, F18 displayed a highly synergistic antiviral effect with nevirapine against nevirapine-resistant virus (Y181C). Furthermore, in silico docking analysis suggested that F18 may bind to the HIV-1 reverse transcriptase differently from other NNRTIs. This study presents F18 as a new potential drug for clinical use and also presents a new mechanism-based design for future NNRTI. Copyright © 2012, American Society for Microbiology. All Rights Reserved.

Citation Format(s)

F18, a novel small-molecule nonnucleoside reverse transcriptase inhibitor, inhibits HIV-1 replication using distinct binding motifs as demonstrated by resistance selection and docking analysis. / Lu, Xiaofan; Liu, Li; Zhang, Xu; Lau, Terrence Chi Kong; Tsui, Stephen Kwok Wing; Kang, Yuanxi; Zheng, Purong; Zheng, Bojian; Liu, Gang; Chen, Zhiwei.

In: Antimicrobial Agents and Chemotherapy, Vol. 56, No. 1, 01.2012, p. 341-351.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review