Abstract
6-(cyclohexylmethyl)-5-ethyl-2-((2-oxo-2-phenylethyl)thio)pyrimidin-4(3H)-one (DB-02) is a member of the newly reported synthetic anti-HIV-1 compounds dihydro-aryl/alkylsulfanyl-cyclohexylmethyl-oxopyrimidines, S-DACOs. 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 site-directed mutagenesis, genotypic resistance profiles revealed that V106A was the major resistance contributor 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.
Highlights
Acquired immunodeficiency syndrome (AIDS) was first reported in 1981 and currently there are 34 million people living with the infection [1]
DB-02 displayed potencies for inhibition of wild-type HIV-1IIIB and HIV-1MN (Table 1), and its EC50 values were in the nanomolar range (2.40 to 5.62 nM)
HIV-1 subtype B is widespread in North America and Europe, while some circulating recombinant forms, such as subtype CRF01_AE and CRF07_BC, are more prevalent in China [20,21]
Summary
Acquired immunodeficiency syndrome (AIDS) was first reported in 1981 and currently there are 34 million people living with the infection [1]. Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are the major components of HAART in clinical therapy. The rapid emergence of mutations, such as K103N and Y181C mutations, has decreased the efficiency of the treatment and often leads to failure of the therapy [5] This adverse effect reduced the clinical usage of first generation NNRTIs. More effective second-generation NNRTIs, etravirine and rilpivirine, were developed to overcome this difficulty. More effective second-generation NNRTIs, etravirine and rilpivirine, were developed to overcome this difficulty They are not available in high prevalence AIDS countries, such as China, due to their high costs. Exhibited high potent activity [10] In this continued DB-02 evaluation study, we put more effort on the in vitro cytotoxicity and antiviral activity of DB-02 on different cell lines, including different subtype strains, clinical strains, and resistant strains. Drug combination activity and molecular docking results of DB-02 are reported
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