Abstract
Non-nucleoside reverse transcriptase inhibitor (NNRTI) is one of the key components of antiretroviral therapy drug regimen against human immunodeficiency virus type-1 (HIV-1) replication. We have 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. Here, we further investigated its antiviral breadth, drug resistance profile and underlying mechanism of action. F18 consistently displayed a potent activity against primary HIV-1 isolates including various subtypes of M group, CRF01_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 (EC50=1.0nM), which was in stark contrast from the extensively used NNRTIs nevirapine and efavirenz. Moreover, we induced F18-resistant viruses by in vitroserial passages, and found that mutation L100I appeared to be the dominant contributor to F18-resistance, further suggesting a binding motif different from nevirapine and efavirenz. The efficacy of F18 was non-antagonistic when used in combination with other antiretrovirals against both wild-type and drug-resistant viruses in infected PBMCs. 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 in a way different to other NNRTIs. This study presents F18 as a new potential drug for clinical use and also underlies new mechanism-based design for future NNRTI.
