The goals of the proposed research are to develop libraries of potential inhibitors for both HIV reverse transcriptase (HIV-RT) and HIV integrase HIV-IN enzymes. The libraries will be created using a common Horner-Emmons-Wittig reagent developed in applicant's laboratories. This reagent provides a rapid synthetic sequence into three diverse classes of compounds including: 1. Symmetrical and unsymmetrical disulfones based on known catechol HIV-IN inhibitors, 2. Novel isosteric analogs of nucleoside triphosphates as HIV-RT inhibitors, and 3. Non-nucleoside HIV-RT inhibitors.
The specific aims are: (a) To synthesize and test novel 5'-disulfone-monophosphate isosteres of nucleic acid triphosphates as nucleoside HIV-RT inhibitors; (b) To synthesize and test a library of gem-disulfone linked aryl acids as non-nucleoside HIV-RT inhibitors; (c) To synthesize and test a gem-disulfone linked library of catechol analogs as HIV-IN inhibitors; (d) To synthesize and test possible bifunctional HIV-IN/HIV-RT inhibitors; (e) To synthesize and test potential suicide inhibitors. We are uniquely positioned to rapidly synthesize a large number of compounds. The investigators have prepared two compounds that show micromolar inhibition of HIV-IN. Testing of these compounds was done at NIH using standard assays. A letter of collaboration to test future HIV-IN inhibitors is attached. Testing for HIV-RT inhibition will be done in their laboratory using the NEN Lifesciences RT-Detect Reverse Transcriptase Assay Kit (CAT. #NEK-070).

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory/Developmental Grants (R21)
Project #
7R21GM060917-03
Application #
6495950
Study Section
Special Emphasis Panel (ZRG1-AARR-3 (01))
Program Officer
Schwab, John M
Project Start
2000-04-01
Project End
2003-03-31
Budget Start
2001-07-01
Budget End
2003-03-31
Support Year
3
Fiscal Year
2001
Total Cost
$110,938
Indirect Cost
Name
University of California Davis
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618
Wong, Jessica H; Sahni, Urvashi; Li, Yanhong et al. (2009) Synthesis of sulfone-based nucleotide isosteres: identification of CMP-sialic acid synthetase inhibitors. Org Biomol Chem 7:27-9
Meadows, D Christopher; Sanchez, Tino; Neamati, Nouri et al. (2007) Ring substituent effects on biological activity of vinyl sulfones as inhibitors of HIV-1. Bioorg Med Chem 15:1127-37