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Michael A. Parniak, Ph.D.
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Professor
W1142 BSTWR
200 Lothrop Street
Pittsburgh, Pennsylvania 15261
Phone: (412) 648-8884
Fax: (412) 648-9653
E-mail: map167@pitt.edu
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Biography
Michael A. Parniak is a Professor of Microbiology and Molecular Genetics at the University of Pittsburgh, School of Medicine. He received a PhD in Bio-Organic Chemistry from the University of Waterloo (Canada) and postdoctoral training at the National Institutes of Health. Prior to moving to the University of Pittsburgh in 2001, he was Professor of Medicine and Biochemistry at McGill University in Canada where he also held the position of International Research Scholar of the Howard Hughes Medical Institute. Dr. Parniak has varied research interests and expertise mainly in HIV/AIDS including antiviral drug discovery, identification and validation of new HIV targets, and mechanisms of antiretroviral drug resistance. He has published over 130 papers and holds 15 patents issued or filed, primarily in the area of antiviral drug discovery, and has founded two biotechnology companies. He is Editor of the International Journal of Biochemistry and Cell Biology and member of the NIH AIDS Molecular and Cell Biology grant review panel.
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Research
Our research is rather 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:
1. Identification and characterization of “drug-like” compounds that inhibit HIV RT-associated ribonuclease H activity. These inhibitors are active against all known clinically important drug-resistant strains of HIV.
2. Identification and characterization of compounds that inhibit the phosphorolytic excision of chain-terminating nucleotides, the major mechanism for HIV resistance to nucleoside analog inhibitors such as AZT. These inhibitors restore antiviral activity of drugs such as AZT against clinically important AZT-resistant HIV strains.
3. Pre-clinical development of the potent nonnucleoside reverse transcriptase inhibitor UC781 as a microbicide to prevent sexual transmission of HIV.
4. Development and characterization of novel nucleoside and nucleotide analogs with antiretroviral activity against current clinically significant drug resistant HIV strains.
We are also actively investigating the mechanisms of HIV resistance to clinically used and experimental antiretroviral agents. Studies include mechanistic analyses of the phenotypes arising from different mutations associated with resistance to nucleoside RT inhibitors, especially mutations associated with multidrug resistance, and the role of multiple mutations in resistance to tight-binding nonnucleoside RT inhibitors. These studies assist in the design of new structural variants of inhibitors with improved properties against drug-resistant HIV.
Finally, we continue to identify and validate novel HIV targets for drug discovery. We are using a novel approach involving the generation and characterization of antibody-derived “intrabodies” targeting specific viral protein domains as probes for potential drug susceptibility.
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.
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Selected Publications
- Sarafianos SG, Marchand B, Das K, Himmel DM, Parniak MA, Hughes SH, Arnold E. 2009. "Structure and function of HIV-1 reverse transcriptase: molecular mechanisms of polymerization and inhibition"J Mol Biol. 385:693-713. | Abstract
- Yang H, Parniak MA, Isaacs CE, Hillier SL, Rohan LC. 2008. "Characterization of cyclodextrin inclusion complexes of the anti-HIV non-nucleoside reverse transcriptase inhibitor UC781" AAPS J. 10:606-13. | Abstract
- Song Y, Chan JM, Tovian Z, Secrest A, Nagy E, Krysiak K, Bergan K, Parniak MA, Oldfield E. 2008. "Bisphosphonate inhibitors of ATP-mediated HIV-1 reverse transcriptase catalyzed excision of chain-terminating 3'-azido, 3'-deoxythymidine: a QSAR investigation" Bioorg Med Chem. 16:8959-67. | Abstract
- Garforth SJ, Parniak MA, Prasad VR. 2008 "Utilization of a deoxynucleoside diphosphate substrate by HIV reverse transcriptase" PLoS ONE. 3:e2074. | Abstract
- Ilina T, Parniak MA. 2008. "Inhibitors of HIV-1 reverse transcriptase" Adv Pharmacol. 56:121-67. | Abstract
- Han Q, Sarafianos SG, Arnold E, Parniak MA, Gaffney BL, Jones RA. 2007. "Synthesis of AZTpSpCX2ppSA and AZTpSpCX2ppSAZT: hydrolysis-resistant potential inhibitors of the AZT excision reaction of HIV-1 RT" Org Lett. 9:5243-6. | Abstract
- Patton DL, Sweeney YT, Balkus JE, Rohan LC, Moncla BJ, Parniak MA, Hillier SL. 2007. "Preclinical safety assessments of UC781 anti-human immunodeficiency virus topical microbicide formulations" Antimicrob Agents Chemother. 51:1608-15. | Abstract
- Dharmasena S, Pongracz Z, Arnold E, Sarafianos SG, Parniak MA. 2007. "3'-Azido-3'-deoxythymidine-(5')-tetraphospho-(5')-adenosine, the product of ATP-mediated excision of chain-terminating AZTMP, is a potent chain-terminating substrate for HIV-1 reverse transcriptase" Biochemistry 46:828-36. | Abstract
- Himmel DM, Sarafianos SG, Dharmasena S, Hossain MM, McCoy-Simandle K, Ilina T, Clark AD Jr, Knight JL, Julias JG, Clark PK, Krogh-Jespersen K, Levy RM, Hughes SH, Parniak MA, Arnold E. 2006. "HIV-1 reverse transcriptase structure with RNase H inhibitor dihydroxy benzoyl naphthyl hydrazone bound at a novel site" ACS Chem Biol. 1:702-12. | Abstract
- Garforth SJ, Kim TW, Parniak MA, Kool ET, Prasad VR. 2007. "Site-directed mutagenesis in the fingers subdomain of HIV-1 reverse transcriptase reveals a specific role for the beta3-beta4 hairpin loop in dNTP selection" J Mol Biol. 365:38-49. | Abstract
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