DB-02, a C-6-cyclohexylmethyl substituted pyrimidinone HIV-1 reverse transcriptase inhibitor with nanomolar activity, displays an improved sensitivity against K103N or Y181C than S-DABOs

Xing-Jie Zhang; Li-He Lu; Rui-Rui Wang; Yue-Ping Wang; Rong-Hua Luo; Christopher Cong Lai; Liu-Meng Yang; Yan-Ping He; Yong-Tang Zheng

doi:10.1371/journal.pone.0081489

DB-02, a C-6-cyclohexylmethyl substituted pyrimidinone HIV-1 reverse transcriptase inhibitor with nanomolar activity, displays an improved sensitivity against K103N or Y181C than S-DABOs

PLoS One. 2013 Nov 25;8(11):e81489. doi: 10.1371/journal.pone.0081489. eCollection 2013.

Authors

Xing-Jie Zhang¹, Li-He Lu, Rui-Rui Wang, Yue-Ping Wang, Rong-Hua Luo, Christopher Cong Lai, Liu-Meng Yang, Yan-Ping He, Yong-Tang Zheng

Affiliation

¹ Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, P. R. China ; University of Chinese Academy of Sciences, Beijing, P. R. China.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetophenones / pharmacology*
Cell Line
HIV Reverse Transcriptase / antagonists & inhibitors*
HIV-1 / drug effects
Humans
Microbial Sensitivity Tests
Molecular Docking Simulation
Mutagenesis, Site-Directed
Pyrimidinones / pharmacology*
Reverse Transcriptase Inhibitors / pharmacology*

Substances

6-(cyclohexylmethyl)-5-ethyl-2-((2-oxo-2-phenylethyl)thio)pyrimidin-4(3H)-one
Acetophenones
Pyrimidinones
Reverse Transcriptase Inhibitors
reverse transcriptase, Human immunodeficiency virus 1
HIV Reverse Transcriptase

Grants and funding

This work was supported in part by grants from the 973 Program (2009CB522306), the Key Scientific and Technological Program of China (2012ZX10001-006; 2012ZX10001-007, 2012ZX09103-101-068) and of Yunnan Province (2009BC018, 2010GA001, Y103951111), the National Science Foundation of China (21262044, 30560179, 30960459, 81001462, 81102483) and the Chinese Academy of Sciences (W8090303). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.