The overall goal of this project is to develop promising drug leads via three-dimensional RNA structure based computational screening of commercially available compounds for binding to selected RNA targets utilizing the 3D structure of portions of the HIV-1 genome. Candidates are small water-soluble, nonpeptide, nonnucleotide organic compounds. These compounds should also represent promising scaffolds for subsequent chemical modification to enhance their pharmaceutical properties. The project entails work on improving the methodology for efficient targeting of RNA. This includes working to make the well-known DOCK program more useful for targeting RNA. It also entails continued development of a new program that enables screening of a smaller database of compounds (up to 10,000) permitting induced fit with the receptor. However, we are quite interested in using the methodology even at its current stage to discover new lead compounds that bind to important HIV RNA structures and thus could be developed into drugs. The most promising computational """"""""hits"""""""" are purchased and tested for binding to the target RNA via various assays we have developed, including NMR. Experiments will continue on compounds already identified to bind to TAR RNA and to the kissing loop duplex that is essential for assembly of the genomic RNA duplex in the budding virion. Among compounds to be examined are several phenothiazines that have been or are being synthesized to establish a structure-activity relationship for binding to TAR; phenothiazine is a promising scaffold for drug development due to low toxicity and good bioavailability. A library of low molecular weight compounds, with good bioavailability and low toxicity and the capability of being linked, that have been found to bind RNA will be developed. The mechanism of the transformation of the kissing loop dimer to the linear dimer, required for assembly of the budding virion, will be studied using a newly found small molecule agonist that promotes the transformation as does the nucleocapsid protein NCp7. ? ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI046967-06
Application #
6891991
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Miller, Roger H
Project Start
2000-01-01
Project End
2009-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
6
Fiscal Year
2005
Total Cost
$464,732
Indirect Cost
Name
University of California San Francisco
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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