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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32AI104334-02
Application #
8588784
Study Section
Special Emphasis Panel (ZRG1-AARR-C (22))
Program Officer
Nasr, Mohamed E
Project Start
2012-12-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
2
Fiscal Year
2014
Total Cost
$49,214
Indirect Cost
Name
Yale University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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