Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are the major components of highly active antiretroviral therapy (HAART) used to control human immunodeficiency virus (HIV) infections. However, the rapid emergence of resistant viruses of NNRTIs has decreased the efficiency of HAART and lead to failure of the therapy. To overcome this difficulty, it is necessary to develop new compounds with a high genetic barrier. Natural products from herbal plants are a great reservoir of medicinal compounds. In traditional Chinese medicine, Wuweizi (Schisandraceae plant) is commonly used to cure chronic cough and dyspnea, spermatorrhea, enuresis, frequent urination, protracted diarrhea and so on. Lignans are the major and characteristic constituents of Schisandraceae plants, also included are organic acids, glycosides and triterpenes. We have reported a new class of molecules, dihydro-aryl/alkylsulfanyl-cyclohexylmethyl-oxopyrimidines (S-DACOs), as novel anti-HIV-1 compounds. 6-(cyclohexylmethyl)-5-ethyl-2-((2-oxo-2-phenylethyl)thio) pyrimidin-4(3H)-one (DB-02) was one of the best compounds with high antiviral activity. In vitro anti-HIV-1 activity and resistance profile studies have suggested that DB-02 has very low cytotoxicity (CC50>1mM) to cell lines and peripheral blood mononuclear cells (PBMCs). It displays potent anti-HIV-1 activity against laboratory adapted strains and primary isolated strains including different subtypes and tropism strains (EC50s range from 2.40 to 41.8 nM). Studies on genotypic resistance profiles and site-directed mutagenesis revealed that V106A was the major mutation of RT for the compound. Molecular docking analysis showed that DB-02 located in the hydrophobic pocket with interactions of Lys101, Val106, Leu234, His235. DB-02 also showed non-antagonistic effects to four approved antiretroviral drugs. All studies indicated that DB-02 would be a potential NNRTI with low cytotoxicity and improved activity. Our results here could also give a clue to optimize S-DACOs compounds to obtain higher genetic barrier and lower cytotoxicity. Our previous study has demonstrated that lignans from Schisandra rebriflora and Schisandra micrantha show anti-HIV activities. During optimization of lignans, we developed a series of novel compounds that inhibit HIV replication in vitro. Among these compounds, SJP-L-5 showed obvious antiviral activity than others. In this study, we found that SJP-L-5 blocked HIV-1 lab strains and clinical isolates replication with EC50 varying from 0.4~16.2 μM, while it also exhibited low cytotoxic to cell lines and primary PBMCs with CC50 higher than 608 μM. SJP-L-5 showed low sensitivity to HIV-1A17, which is an NNRTI resistant strain, indicating that it might be an RT inhibitor. However, it did not inhibit RT RNA dependent DNA polymerase activity in vitro. This contradiction suggests that SJP-L-5 may have a special mechanism of action against RT. We next found that SJP-L-5 could inhibit RT DNA dependent DNA polymerase activity, but not its RNaseH activity. In conclusion, SJP-L-5 is a novel and special RT inhibitor based on lignan structure and its antiviral mechanism needs to be further investigated.
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