Abstract

The current proposal seeks to continue mechanistic studies to understand, at the molecular level, the enzyme activities of RT and interaction of nucleoside inhibitors and the resistance of these compounds which develop through mutations. To achieve these aims, the investigator proposes (1) studies of the process of tRNA3lys initiation of HIV RT using an RNA duplex substrate. Because the tRNA will most likely have substantial secondary structures, the functional properties of this RNA duplex interaction with HIV RT may be different than the DNA duplex or RNA/DNA heteroduplex substrates previously used. (2) The relevance of the nucleocapsid protein as it is involved in both the rRNA3lys initiation and elongation processes and its role in the development of mutant RT. (3) Mechanistic studies will be conducted on the inhibition of mitochondrial gamma polymerase by nucleoside analogues which may be important to understand cytotoxicity.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM049551-06
Application #
2685021
Study Section
AIDS and Related Research Study Section 4 (ARRD)
Project Start
1993-04-01
Project End
2000-03-31
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
6
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
Yale University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520

  Publications

Kudalkar, Shalley N; Beloor, Jagadish; Quijano, Elias et al. (2018) From in silico hit to long-acting late-stage preclinical candidate to combat HIV-1 infection. Proc Natl Acad Sci U S A 115:E802-E811
Baranovskiy, Andrey G; Duong, Vincent N; Babayeva, Nigar D et al. (2018) Activity and fidelity of human DNA polymerase ? depend on primer structure. J Biol Chem 293:6824-6843
Chan, Albert H; Lee, Won-Gil; Spasov, Krasimir A et al. (2017) Covalent inhibitors for eradication of drug-resistant HIV-1 reverse transcriptase: From design to protein crystallography. Proc Natl Acad Sci U S A 114:9725-9730
Kudalkar, Shalley N; Beloor, Jagadish; Chan, Albert H et al. (2017) Structural and Preclinical Studies of Computationally Designed Non-Nucleoside Reverse Transcriptase Inhibitors for Treating HIV infection. Mol Pharmacol 91:383-391
Mislak, Andrea C; Anderson, Karen S (2016) Insights into the Molecular Mechanism of Polymerization and Nucleoside Reverse Transcriptase Inhibitor Incorporation by Human PrimPol. Antimicrob Agents Chemother 60:561-9
Li, Min; Mislak, Andrea C; Foli, Yram et al. (2016) The DNA Polymerase Gamma R953C Mutant Is Associated with Antiretroviral Therapy-Induced Mitochondrial Toxicity. Antimicrob Agents Chemother 60:5608-11
Lee, Won-Gil; Frey, Kathleen M; Gallardo-Macias, Ricardo et al. (2015) Discovery and crystallography of bicyclic arylaminoazines as potent inhibitors of HIV-1 reverse transcriptase. Bioorg Med Chem Lett 25:4824-7
Frey, Kathleen M; Puleo, David E; Spasov, Krasimir A et al. (2015) Structure-based evaluation of non-nucleoside inhibitors with improved potency and solubility that target HIV reverse transcriptase variants. J Med Chem 58:2737-45
Sohl, Christal D; Szymanski, Michal R; Mislak, Andrea C et al. (2015) Probing the structural and molecular basis of nucleotide selectivity by human mitochondrial DNA polymerase ?. Proc Natl Acad Sci U S A 112:8596-601
Muftuoglu, Yagmur; Sohl, Christal D; Mislak, Andrea C et al. (2014) Probing the molecular mechanism of action of the HIV-1 reverse transcriptase inhibitor 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) using pre-steady-state kinetics. Antiviral Res 106:1-4

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