This project will examine the pharmacokinetics (PK), safety, and efficacy of new small molecule inhibitors of mixed lineage kinase type 3 (MLKS), in animal models of neuroAIDS. The works will bridge studies in Project 1 that investigate the mechanism of MLKS activation (referred to as descendant congeners of our current lead compound URMC-099: URMC-099c*) developed in Project 2 (Califia Bio). Based on efficacy measures established in Project 1, the most promising URMC-099c* compounds will be advanced to our models of peripheral and CNS viral infection. MLKS is critically linked to HIV-1 neuropathology as its pathologic activation is operative during HIV-1 infection ofthe central nervous system and results in neuroinflammation, impaired synaptic plasticity, and neuronal dysfunction;all hallmarks of HlV-1 associated neurocognitive disease (HAND). We will assess the neuroprotective properties of these new generation of MLKS inhibitor compounds as adjunctive therapeutics for HAND. Well-developed animal model systems of neuroAIDS (rodents and monkeys) will serve as the testing platform. Because these model systems use CNS viral infection to produce models of HAND, they will directly support translational (bench to beside) research efforts for subsequent clinical trials. The organization of all experimental protocols supports the concept that virus-infected mononuclear phagocytes [(MP) (microglia, perivascular and parenchymal macrophages)] serve both as reservoirs for productive HlV-1 infection and as principal sources of neurotoxic activities within the central nervous system. Our laboratories, over the past decade, through strong collaborations with University of Rochester Medical Center investigators, developed the necessary model systems that mirror the biologic, immune, and physiologic effects of HIV-1 replication in brain MP relevant to HAND and as such enabled, during the prior funding cycle, the translation of animal studies to human clinical trials. Integrated bioimaging, virologic and immune testing performed on neuroAIDS mice and simian immunodeficiency virus-infected rhesus macaques will investigate how such neuroprotective therapies can be optimally utilized as treatments for HI V-1-associated neurocognitive impairments in humans. At the conclusion of our studies, we expect to bring forward the most promising URMC-099c* as the candidate for IND filing with the FDA.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Program Projects (P01)
Project #
5P01MH064570-13
Application #
8664425
Study Section
Special Emphasis Panel (ZMH1-ERB-M)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
13
Fiscal Year
2014
Total Cost
$381,633
Indirect Cost
Name
University of Rochester
Department
Type
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Zhang, Gang; Guo, Dongwei; Dash, Prasanta K et al. (2016) The mixed lineage kinase-3 inhibitor URMC-099 improves therapeutic outcomes for long-acting antiretroviral therapy. Nanomedicine 12:109-22
Dong, Weiguo; Embury, Christine M; Lu, Yaman et al. (2016) The mixed-lineage kinase 3 inhibitor URMC-099 facilitates microglial amyloid-β degradation. J Neuroinflammation 13:184
Guo, Dongwei; Zhou, Tian; Araínga, Mariluz et al. (2016) Creation of a Long-Acting Nanoformulated 2',3'-Dideoxy-3'-Thiacytidine. J Acquir Immune Defic Syndr :
Araínga, Mariluz; Su, Hang; Poluektova, Larisa Y et al. (2016) HIV-1 cellular and tissue replication patterns in infected humanized mice. Sci Rep 6:23513
Olson, Katherine E; Gendelman, Howard E (2016) Immunomodulation as a neuroprotective and therapeutic strategy for Parkinson's disease. Curr Opin Pharmacol 26:87-95
Olson, Katherine E; Bade, Aditya N; Schutt, Charles R et al. (2016) Manganese-Enhanced Magnetic Resonance Imaging for Detection of Vasoactive Intestinal Peptide Receptor 2 Agonist Therapy in a Model of Parkinson's Disease. Neurotherapeutics 13:635-46
Li, Weizhe; Tong, Hsin-I; Gorantla, Santhi et al. (2016) Neuropharmacologic Approaches to Restore the Brain's Microenvironment. J Neuroimmune Pharmacol 11:484-94
Singh, Dhirender; McMillan, JoEllyn; Hilaire, James et al. (2016) Development and characterization of a long-acting nanoformulated abacavir prodrug. Nanomedicine (Lond) 11:1913-27
Sajja, Balasrinivasa R; Bade, Aditya N; Zhou, Biyun et al. (2016) Generation and Disease Model Relevance of a Manganese Enhanced Magnetic Resonance Imaging-Based NOD/scid-IL-2Rγc(null) Mouse Brain Atlas. J Neuroimmune Pharmacol 11:133-41
Bade, Aditya N; Gorantla, Santhi; Dash, Prasanta K et al. (2016) Manganese-Enhanced Magnetic Resonance Imaging Reflects Brain Pathology During Progressive HIV-1 Infection of Humanized Mice. Mol Neurobiol 53:3286-97

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