The continuous emergence of HIV phenotypes resistant to the current anti-HIV drugs dictates a need to develop new therapies with alternative mechanisms of inhibition. HIV integrase (IN) is commonly viewed as an important antiviral target for the following reasons: its catalytic activities are required for viral replication, there is no closely related cellular equivalent of IN, and specific IN inhibitors are likely to be effective against viral strains resistant to currently available therapies. The present proposal focuses on exploiting HIV IN multimers as a new therapeutic target. The main novelty of my approach is to stabilize rather than destabilize IN multimers in the inactive conformation. The rationale for this has been provided by my recent findings which demonstrated that unliganded IN subunits have to be highly dynamic and flexible in order to form functional multimers in the presence of viral DNA. Restricting IN flexibility adversely affects its catalytic activities. As a proof of principle I have reported a small molecule inhibitor (compound 1) that effectively binds at the IN dimer interface and stabilizes interacting subunits into an inactive conformation. These findings led me to the following hypothesis: HIV IN possesses unique structural pockets that can be selectively targeted by small molecules to inhibit viral integration by locking IN into an unproductive multimeric state. To address this hypothesis, my preliminary studies have identified two separate sites (which are termed here as "bottom" and "side" pockets) at the IN dimer interface suitable for binding of small allosteric inhibitors.
Aim 1 will focus to increase the binding specificity and affinity of compound 1 for the "bottom" pocket;
aim 2 will rationally design new allosteric molecules selectively binding the "side" pocket.

Public Health Relevance

Emergence of HIV-1 strains resistant to the current antiretroviral therapies is a serious clinical problem. Therefore, there is an urgent need to identify and validate new viral targets for drug discovery. One such target investigated in the present proposal is a multimeric structure of a key HIV-1 enzyme integrase.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI097044-02
Application #
8294551
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Gupta, Kailash C
Project Start
2011-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$228,750
Indirect Cost
$78,750
Name
Ohio State University
Department
None
Type
Schools of Pharmacy
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Feng, Lei; Sharma, Amit; Slaughter, Alison et al. (2013) The A128T resistance mutation reveals aberrant protein multimerization as the primary mechanism of action of allosteric HIV-1 integrase inhibitors. J Biol Chem 288:15813-20
Jurado, Kellie A; Wang, Hao; Slaughter, Alison et al. (2013) Allosteric integrase inhibitor potency is determined through the inhibition of HIV-1 particle maturation. Proc Natl Acad Sci U S A 110:8690-5
Kessl, Jacques J; Jena, Nivedita; Koh, Yasuhiro et al. (2012) Multimode, cooperative mechanism of action of allosteric HIV-1 integrase inhibitors. J Biol Chem 287:16801-11