PhD in Chemistry, University of Waterloo, Waterloo (Ontario, Canada)
Professor, Department of Microbiology and Molecular Genetics
Professor, Graduate School of Public Health, Department of Infectious Diseases & Microbiology
Adjunct Professor, University of Waterloo, Departments of Chemistry and Pharmaceutical Sciences
Member, Molecular Virology and Microbiology Graduate Program
Our research is primarily translational and concerns the discovery and development of small molecule drugs and biologicals directed at novel HIV targets. Our research is by necessity multidisciplinary involving biochemistry, biophysics, chemistry, molecular biology, molecular virology and structural biology to develop new drugs against HIV. Current projects include:
- Identification, characterization and preclinical development of “drug-like” compounds that inhibit HIV RT-associated ribonuclease H activity. Our screening activities have to date identified over 600 such inhibitors, most of which are active against all known clinically important drug-resistant mutants.
- Preclinical development studies with the potent nucleoside reverse transcriptase inhibitor, 4’-ethynyl-2-fluoro-2’-deoxyadenosine (EFdA)
- Pre-clinical development of the nonnucleoside reverse transcriptase inhibitor CSIC and the nucleoside EFdA in combination, and CSIC and the entry inhibitor RC101 in combination, for use as topical microbicides to prevent sexual transmission of HIV.
We have recently begun investigations into (a) the role of HIV polyprotein interactions during virus assembly and evaluation of the impact of small molecules on these interactions, and (b) structure-function studies of initiation of reverse transcription and the development of HTS assays to identify specific inhibitors of this critical process in HIV replication.
Techniques: High throughput screening, transient (pre-steady state) kinetic analysis of enzyme function, biochemical and biophysical probes of protein structure and function (fluorescence, crystallography, NMR), molecular modeling of drug-receptor interactions, site-specific mutagenesis, cell and virus culture, antiviral drug susceptibility assays, development and characterization of HIV resistance to novel antiviral agents.
Tatiana Ilina, PhD - Research Associate
Lena Miller, PhD - Research Specialist
Evan Nagy - Research Specialist
Aaron Reeve, PhD - Postdoctoral Fellow
Areas of Interest
HIV reverse transcriptase structure-function; HIV ribonuclease H; drug discovery and development; molecular mechanisms of HIV drug resistance; development of microbicides to prevent sexual transmission of HIV.
Murphey-Corb M, Rajakumar P, Michael H, Nyaundi J, Didier P. J, Reeve A. B, Mitsuya H, Sarafianos S. G, and Parniak M. A. Response of simian immunodeficiency virus to the novel nucleoside reverse transcriptase inhibitor 4'-ethynyl-2-fluoro-2'-deoxyadenosine in vitro and in vivo. Antimicrob Agents Chemother. 56: 4707-4712. | View Abstract
Li M, Shandilya S. M, Carpenter M. A, Rathore A, Brown W. L, Perkins A. L, Harki D. A, Solberg J, Hook D. J, Pandey K. K, Parniak M. A, Johnson J. R, Krogan N. J, Somasundaran M, Ali A, Schiffer C. A, Harris R. S. First-in-class small molecule inhibitors of the single-strand DNA cytosine deaminase APOBEC3G. ACS Chem Biol. 7: 506-517. | View Abstract
Kirby K. A, Marchand B, Ong Y. T, Ndongwe T. P, Hachiya A, Michailidis E, Leslie M. D, Sietsema D. V, Fetterly T. L, Dorst C. A, Singh K, Wang Z, Parniak M. A, and Sarafianos S. G. Structural and inhibition studies of the RNase H function of xenotropic murine leukemia virus-related virus reverse transcriptase. Antimicrob Agents Chemother. 56: 2048-2061. | View Abstract
Christen M. T, Menon L, Myshakina N. S, Ahn J, Parniak M. A, Ishima R. Structural Basis of the Allosteric Inhibitor Interaction on the HIV-1 Reverse Transcriptase RNase H Domain. Chem Biol Drug Dis. 80: 706-716. | View Abstract
Bunge K, Macio I, Meyn L, Noguchi L, Parniak M. A, Schwartz J. L, Moncla B, and Hillier S. The safety, persistence, and acceptability of an antiretroviral microbicide candidate UC781. J Acquir Immune Defic Syndr. 60: 337-343. | View Abstract
Felts A. K, Labarge K, Bauman J. D, Patel D. V, Himmel D. M, Arnold E, Parniak M. A, and Levy R. M. Identification of alternative binding sites for inhibitors of HIV-1 ribonuclease H through comparative analysis of virtual enrichment studies. J Chem Inf Model. 51: 1986-1998. | View Abstract
Abram M. E, Sarafianos S. G, and Parniak M. A. The mutation T477A in HIV-1 reverse transcriptase (RT) restores normal proteolytic processing of RT in virus with Gag-Pol mutated in the p51-RNH cleavage site. Retrovirology. 7 | View Abstract