PROVIDED. This application proposes the identification and preclinical development of novel small molecule antagonists of the Vif protein of HIV-1. Apobec 3G is a cytidine deaminase which potently antagonizes HIV-1 infection. To counteract this cellular restriction, primate lentiviruses such as HIV-1 have evolved a Vif protein, the function of which is to target apobec for proteasomal destruction. Viruses containing mutations in Vif are severely compromised in vitro and in vivo. Therefore, Vif is a critical, yet unrealized, therapeutic target. Through institutional support and a grant from Howard Hughes Medical Institute, UMass Medical School (UMMS) has recently established a high throughput inhibitor screening facility and the identification of compounds that block the action of HIV-1 Vif was prioritized. As a result of this initial screening, two lead compounds that block Vif-mediated apobec destruction have been identified. These compounds inhibit HIV- 1 replication only in the presence of apobec and as such, are bona fide Vif inhibitors. This provides proof-ofprinciple that novel inhibitors of the HIV-1 Vif protein can be identified. This program project application will combine individuals with expertise in drug discovery, HIV-1 virology and SIV immunopathogenesis for the preclinical development of novel antagonists of HIV-1 Vif. The program project comprises: Project 1, T. Rana, Ph.D., UMMS, Vif antagonists: lead inhibitor identification and SAR analysis. Project 2, M. Stevenson, Ph.D., UMMS, Vif antagonists: evaluation of antiviral activity and mechanism of action in vitro. Mechanisms of inhibitor resistance in vitro and in vivo. Project 3, K. Mansfield, D.V.M., Harvard and NEPRC, Vif-antagonists: small animal PK and toxicity profiling, evaluation in chronic SIV infection model and in model of SIV-induced encephalitis. Core A, Administrative Core Core B, B. Beer, Ph.D., Southern Research Institute, Vif-antagonists: inhibitor sensitivity of clinical HIV-1 isolates, and plasma SIV RNA assays in treated monkeys. Through this program project, we propose the preclinical development of a new class of compounds that antagonize HIV-1 and SIV Vif and which will be used to assess the consequences of Vif antagonism in lymphoid and CNS reservoirs of viral replication in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19MH081836-05
Application #
8271417
Study Section
Special Emphasis Panel (ZAI1-TP-A (J2))
Program Officer
Colosi, Deborah
Project Start
2007-04-16
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$1,089,177
Indirect Cost
$380,349
Name
University of Miami School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Whisnant, Adam W; Bogerd, Hal P; Flores, Omar et al. (2013) In-depth analysis of the interaction of HIV-1 with cellular microRNA biogenesis and effector mechanisms. MBio 4:e000193
Nathans, Robin; Cao, Hong; Sharova, Natalia et al. (2008) Small-molecule inhibition of HIV-1 Vif. Nat Biotechnol 26:1187-92