HIV/AIDS remains a global epidemic and public health threat. Despite the development of effective antiretroviral drugs, therapy is not curative and is therefore life-long. Long-term therapy is often compromised by viral drug resistance mutations and incomplete adherence. The HIV-1 capsid represents an attractive target for therapy, though currently available inhibitors lack sufficient potency for clinical development. This project will develop a competition-based assay for small molecules targeting a specific pocket in the HIV-1 capsid and will adapt the assay for high-throughput screening of large compound libraries. The assay will be validated by screening a library of 10,000 small molecules and analyzing the hits for antiviral activity and cytotoxicity. This work will facilitate the identification of lead compounds for development of antivirals targeting the HIV-1 capsid, and will identify novel probes for HIV-1 capsid function.
Specific Aims :
Aim 1. Establish a competition-based high-throughput screening assay for small molecules that bind the H3-H4 pocket in HIV-1 CA.
Aim 2. Perform pilot screens to validate the assay.
Aim 3. Test the confirmed hits for antiviral activity against wild type HIV- and mutant viruses that are resistant to known capsid inhibitors.

Public Health Relevance

HIV/AIDS remains a global epidemic and public health threat. Effective therapy requires long- term treatment with antiviral drugs, which is often compromised by viral resistance. This project will develop a competition-based assay for small molecules targeting a specific pocket in the HIV-1 capsid and will adapt the assay for high-throughput screening of large compound libraries, thus facilitating the identification of lead compounds for development of antivirals targeting the HIV-1 capsid.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01AI114339-01
Application #
8790352
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Sanders, Brigitte E
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Nashville
State
TN
Country
United States
Zip Code
37212