Reverse transcriptase (RT) is an essential enzyme that copies the viral RNA genome into double stranded DNA via polymerization, a process required for HIV-1 infection. Several enzymes in HIV-1, including RT, are drug targets for highly active antiretroviral therapies (HAART). Non-nucleoside and non-nucleotide RT inhibitors (NNRTIs) are therapeutics prescribed in combination with 3-4 additional antiviral agents that work synergistically to induce viral load suppression in infected patients. Currently, there are fie FDA approved NNRTIs targeting RT, which include nevirapine, delaviridine, efavirenz, etravirine, and rilpivirine. However, there are several limitations to current NNRTIs such as resistance and toxicity issues from long-term usage. The design and development of new NNRTIs with improved resistance and safety profiles is crucial to overcome HIV-1 treatment failure. Over the last few years, we have developed several new compounds as potential NNRTIs using a combination of mechanistic studies, computational chemistry, and structure-based drug design. We have recently designed an NNRTI compound that is active against HIV-1 and has a therapeutic index of 180,000 for cellular toxicity. With an EC50 of 55 pM, this compound emerges as the most potent antiviral agent targeting HIV-1 to date. In order to optimize these compounds into potential drug candidates, this proposal aims to develop structure activity relationships (SAR) and structure property relationships (SPR). Pre-steady state kinetics will determine binding affinity measurements for leading NNRTI compounds and the RT enzyme. In addition to binding affinities, co-crystallization of leading NNRTIs and the RT enzyme will provide a structural interpretation for enzyme-inhibitor interactions and SAR. A series of in vitro analytical and pharmacological techniques will be used to determine SPR for leading compounds. Structure property measurements to be determined include lipophilicity, kinetic solubility, permeability, and metabolic stability. The combination of both SAR and SPR for leading NNRTI compounds will prioritize future development and provide structural information for rational drug design of efficacious NNRTIs.
Non-nucleoside and non-nucleotide reverse transcriptase inhibitors (NNRTIs) are major components of highly active antiretroviral therapy (HAART) that induce viral load suppression in HIV-1 patients. This proposal focuses on developing structure activity relationships (SAR) and structure property relationships (SPR) for novel small molecule compounds with antiviral activity as potential NNRTIs of HIV-1. SAR and SPR studies are critical for drug discovery and development of new NNRTIs that can overcome treatment failure due to resistance and toxicity issues from long-term usage.
|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|
|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; Gray, William T; Spasov, Krasimir A et al. (2014) Structure-based evaluation of C5 derivatives in the catechol diether series targeting HIV-1 reverse transcriptase. Chem Biol Drug Des 83:541-9|
|Kumar, Vidya P; Cisneros, Jose A; Frey, Kathleen M et al. (2014) Structural studies provide clues for analog design of specific inhibitors of Cryptosporidium hominis thymidylate synthase-dihydrofolate reductase. Bioorg Med Chem Lett 24:4158-61|
|Mislak, Andrea C; Frey, Kathleen M; Bollini, Mariela et al. (2014) A mechanistic and structural investigation of modified derivatives of the diaryltriazine class of NNRTIs targeting HIV-1 reverse transcriptase. Biochim Biophys Acta 1840:2203-11|
|Lee, Won-Gil; Gallardo-Macias, Ricardo; Frey, Kathleen M et al. (2013) Picomolar inhibitors of HIV reverse transcriptase featuring bicyclic replacement of a cyanovinylphenyl group. J Am Chem Soc 135:16705-13|
|Bollini, Mariela; Frey, Kathleen M; Cisneros, JosÃ© A et al. (2013) Extension into the entrance channel of HIV-1 reverse transcriptase--crystallography and enhanced solubility. Bioorg Med Chem Lett 23:5209-12|
|Iyidogan, Pinar; Sullivan, Todd J; Chordia, Mahendra D et al. (2013) Design, Synthesis, and Antiviral Evaluation of Chimeric Inhibitors of HIV Reverse Transcriptase. ACS Med Chem Lett 4:1183-8|
|Kumar, Vidya P; Frey, Kathleen M; Wang, Yiqiang et al. (2013) Substituted pyrrolo[2,3-d]pyrimidines as Cryptosporidium hominis thymidylate synthase inhibitors. Bioorg Med Chem Lett 23:5426-8|
|Frey, Kathleen M; Bollini, Mariela; Mislak, Andrea C et al. (2012) Crystal structures of HIV-1 reverse transcriptase with picomolar inhibitors reveal key interactions for drug design. J Am Chem Soc 134:19501-3|