The overall aim of this proposal is to study the biochemical pharmacology of anti-human immunodeficiency virus type 1 (HIV-1) compounds; this includes their mechanism of action, resistance, and toxicity. The current compounds of interest will be anti-HIV-1 nucleoside analogs with a special focus on beta-L(-)dideoxynucleosides. The focus of the proposed studies is the elucidation of key host cellular biochemical determinants that are shared by all anti-HIV-1 nucleoside analogs and the interaction of beta-D(+) and beta-L(-)dideoxynucleoside analogs with these determinants. The following Specific Aims are based on original findings in this laboratory. I. Characterization of cytoplasmic DNA exonucleases, TREx-1 and TREx-2, that may constitute a significant mechanism of viral sensitivity to anti-HIV-1 nucleoside analogs. A. Substate specificity and cellular behavior of TREx-1 and TREx-2 B. Inducibility and regulation of these two exonculeases by HIV-1 and/or anti-HIV-1 nucleoside analogs. C. Role of these two exonuclease enzymatic activities in the sensitivity of HIV-1 to anti-HIV-1 nucleoside analogs and the synergistic antiviral interaction of beta-L(-)dideoxycytidine analogs with d4T. II. Characterization of a mitochondria) deoxynucleoside triphosphate (dNTP) carrier that maybe a significant determinant in the toxicity of anti-HIV-1 nucleoside analogs to mitochondrial function. A. Substrate and inhibitor specificity of the dNTP carrier. B. Molecular characterization of the mitochondrial dNTP carrier with a special focus on a 29 kDa protein (p29). C. Establish the role of p29 as a member of the dNTP carrier and its role in the toxicity of nucleoside analogs against mitochondrial DNA synthesis.
Both Specific Aims are to address the role of two novel host factors in the determination of the efficiency of nucleoside analogs against HIV-1. The information obtained will be useful for our understanding the differences in the effectiveness of anti-HIV-1 nucleoside analogs among different individuals and in a given patient through a period of treatment.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Litterst, Charles L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Schools of Medicine
New Haven
United States
Zip Code
Wang, Ying; Chen, Shao-Ru; Yang, Xiaoming et al. (2018) Structure-activity relationships of cryptopleurine analogs with E-ring modifications as anti-hepatitis C virus agents. Bioorg Med Chem 26:630-636
Wang, Ying; Lam, Wing; Chen, Shao-Ru et al. (2016) Tylophorine Analog DCB-3503 Inhibited Cyclin D1 Translation through Allosteric Regulation of Heat Shock Cognate Protein 70. Sci Rep 6:32832
Tsao, Ning; Lee, Ming-Hsiang; Zhang, Wei et al. (2015) The contribution of CMP kinase to the efficiency of DNA repair. Cell Cycle 14:354-63
Wu, Chien-Huang; Wang, Chuan-Jen; Chang, Chun-Ping et al. (2015) Function-oriented development of CXCR4 antagonists as selective human immunodeficiency virus (HIV)-1 entry inhibitors. J Med Chem 58:1452-65
Fan, Jiyun; Wang, Ying; Xiong, Hui et al. (2014) Impact of the rtI187V polymerase substitution of hepatitis B virus on viral replication and antiviral drug susceptibility. J Gen Virol 95:2523-30
Selvaraj, S; Ghebremichael, M; Li, M et al. (2014) Antiretroviral therapy-induced mitochondrial toxicity: potential mechanisms beyond polymerase-? inhibition. Clin Pharmacol Ther 96:110-20
Haraguchi, Kazuhiro; Takeda, Shingo; Kubota, Yutaka et al. (2013) From the chemistry of epoxy-sugar nucleosides to the discovery of anti-HIV agent 4'-ethynylstavudine-Festinavir. Curr Pharm Des 19:1880-97
Tsou, Lun K; Cheng, Yao; Cheng, Yung-Chi (2012) Therapeutic development in targeting protein-protein interactions with synthetic topological mimetics. Curr Opin Pharmacol 12:403-7
Tsou, Lun K; Chen, Chin-Ho; Dutschman, Ginger E et al. (2012) Blocking HIV-1 entry by a gp120 surface binding inhibitor. Bioorg Med Chem Lett 22:3358-61
Haraguchi, Kazuhiro; Shimada, Hisashi; Kimura, Keiogo et al. (2011) Synthesis of 4'-Ethynyl-2'-deoxy-4'-thioribonucleosides and Discovery of a Highly Potent and Less Toxic NRTI. ACS Med Chem Lett 2:692-697

Showing the most recent 10 out of 32 publications