The objective of this program project application is to develop novel therapeutics that target CNS and peripheral reservoirs of HIV-1 replication. Under the auspices of a U19, we have identified novel small molecules that target the vif-apobec axis and that specifically inhibit vif-dependent viral replication. Structure Activity Relationship (SAR studies have identified potent analogs (IC50 <100nm) that are active in primary'macrophage, show CNS bioavailability and exhibit unique resistance profiles. We propose to build on these discoveries to optimize the activity and specificity of these small molecule vif antagonists and, on the basis of antiviral potency/specificity, Pk/Tox and resistance profiles, prioritize the most promising analogs for analysis efficacy in a SlV/macaque model of encephalitis. The individual projects and cores that constitute this program project application and their roles are as follows: Project 1. Tariq Rana, Ph.D., Sanford-Burnham Institute, Vif antagonism: lead discovery and SAR. Project 2. Mario Stevenson, Ph.D., University of Miami Medical School. Vif antagonism: Virologic support for SAR and molecular mechanisms of inhibitor resistance. Project 3. Susan Westmoreland, VMD, New England Primate Research Center. Vif antagonism: evaluation of efficacy in a macaque model of SIV-induced encephalitis. Core A, Administration. Mario Stevenson, University of Miami Medical School. Coordination of the activities of the individual components and interaction with the external Scientific Advisory Board. Core B. Agneta von Gegerfelt'Ph.D., Bioqual Inc. SIV viral load assays and small animal Pk/Tox studies. Bioqual, Inc. will serve as a non-academic core on this program project application. Studies undertaken in this program project will advance the development of a clinical candidate and set the stage for the clinical evaluation of vif antagonists as new agents for the treatment of HIV-1 infection.
HIV-1-associated CNS disease remains a significant issue in the era of effective ART and a significant proportion of aviremic patients exhibit neurocognitive impairment. Therefore, new agents that prevent viral replication in the CNS and the onset of NeuroAIDS are needed. Our goal is to develop novel therapeutic agents that target CNS as well as peripheral reservoirs of HIV-1 replication by blocking the action of the viral vif protein.
|Sattentau, Quentin J; Stevenson, Mario (2016) Macrophages and HIV-1: An Unhealthy Constellation. Cell Host Microbe 19:304-10|
|Rainho, Jennifer N; Martins, Mauricio A; Cunyat, Francesc et al. (2015) Nef Is Dispensable for Resistance of Simian Immunodeficiency Virus-Infected Macrophages to CD8+ T Cell Killing. J Virol 89:10625-36|
|Stevenson, Mario (2015) Role of myeloid cells in HIV-1-host interplay. J Neurovirol 21:242-8|
|Yang, Chao-Shun; Rana, Tariq M (2013) Learning the molecular mechanisms of the reprogramming factors: let's start from microRNAs. Mol Biosyst 9:10-7|
|Shen, Yang; Altman, Michael D; Ali, Akbar et al. (2013) Testing the substrate-envelope hypothesis with designed pairs of compounds. ACS Chem Biol 8:2433-41|
|Silver, Nathaniel W; King, Bracken M; Nalam, Madhavi N L et al. (2013) Efficient Computation of Small-Molecule Configurational Binding Entropy and Free Energy Changes by Ensemble Enumeration. J Chem Theory Comput 9:5098-5115|
|Nalam, Madhavi N L; Ali, Akbar; Reddy, G S Kiran Kumar et al. (2013) Substrate envelope-designed potent HIV-1 protease inhibitors to avoid drug resistance. Chem Biol 20:1116-24|
|Mohammed, Idrees; Parai, Maloy K; Jiang, Xinpeng et al. (2012) SAR and Lead Optimization of an HIV-1 Vif-APOBEC3G Axis Inhibitor. ACS Med Chem Lett 3:465-469|
|Ali, Akbar; Wang, Jinhua; Nathans, Robin S et al. (2012) Synthesis and structure-activity relationship studies of HIV-1 virion infectivity factor (Vif) inhibitors that block viral replication. ChemMedChem 7:1217-29|