Michael A. Parniak, PhD

Professor Emeritus


Dr. Michael Parniak

Contact

412-648-8884
Fax: 412-648-9653

414 Bridgeside Point II

450 Technology Drive

Pittsburgh, PA 15219-3143

Education

PhD in Chemistry, University of Waterloo (Canada)

Research Summary

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.

Research Lab Affiliation

Publications

Gong, Q; Menon, L; Ilina, T; Miller, L. G; Ahn, J; Parniak, M. A; and Ishima, R. (2011) Interaction of HIV-1 reverse transcriptase ribonuclease H with an acylhydrazone inhibitor. Chem Biol Drug Des. 77: 39-47. |  View Abstract

Abram, M. E; Sarafianos, S. G; and Parniak, M. A. (2010) 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: 6. |  View Abstract

Han, Q; Sarafianos, S. G; Arnold, E; Parniak, M. A; Gaffney, B. L; and Jones, R. A. (2009) Synthesis of Boranoate, Selenoate, and Thioate Analogs of AZTp(4)A and Ap(4)A. Tetrahedron. 65: 7915-7920. |  View Abstract

Michailidis, E; Marchand, B; Kodama, E. N; Singh, K; Matsuoka, M; Kirby, K. A; Ryan, E. M; Sawani, A. M; Nagy, E; Ashida, N; Mitsuya, H; Parniak, M. A; and Sarafianos, S. G. (2009) Mechanism of inhibition of HIV-1 reverse transcriptase by 4'-Ethynyl-2-fluoro-2'-deoxyadenosine triphosphate, a translocation-defective reverse transcriptase inhibitor. J Biol Chem. 284: 35681-35691. |  View Abstract

Sarafianos, S. G; Marchand, B; Das, K; Himmel, D. M; Parniak, M. A; Hughes, S. H; and Arnold, E. (2009) Structure and function of HIV-1 reverse transcriptase: molecular mechanisms of polymerization and inhibition. J Mol Biol. 385: 693-713. |  View Abstract

Yang, H; Parniak, M. A; Isaacs, C. E; Hillier, S. L; and Rohan, L. C. (2008) Characterization of cyclodextrin inclusion complexes of the anti-HIV non-nucleoside reverse transcriptase inhibitor UC781. AAPS J. 10: 606-613. |  View Abstract

Song, Y; Chan, J. M; Tovian, Z; Secrest, A; Nagy, E; Krysiak, K; Bergan, K; Parniak, M. A; and 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: 8959-8967. |  View Abstract