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J Neuroimmune Pharmacol. 2019 Mar;14(1):44-51. doi: 10.1007/s11481-018-09829-8. Epub 2019 Jan 7.

Broad Spectrum Mixed Lineage Kinase Type 3 Inhibition and HIV-1 Persistence in Macrophages.

Author information

1
Center for Neurotherapeutics Discovery and Department of Microbiology & Immunology, University of Rochester Medical Center, Rochester, NY, USA.
2
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
3
Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
4
Center for Neurotherapeutics Discovery, Departments of Neurology, Pediatrics, Neuroscience and Microbiology and Immunology, University of Rochester Medical Center, Box 645, 601 Elmwood Avenue, Rochester, NY, 14642, USA. harris_gelbard@urmc.rochester.edu.

Abstract

Mixed lineage kinases (MLKs) are a group of serine-threonine kinases that evolved in part to respond to endogenous and exogenous insults that result in oxidative stress and pro-inflammatory responses from innate immune cells. Human immunodeficiency virus type 1 (HIV-1) thrives in these conditions and is associated with the development of associated neurocognitive disorders (HAND). As part of a drug discovery program to identify new therapeutic strategies for HAND, we created a library of broad spectrum MLK inhibitors with drug-like properties. Serendipitously, the lead compound, URMC-099 has proved useful not only in reversing damage to synaptic architecture in models of HAND, but also serves to restore autophagy as a protective response when given in concert with nanoformulated antiretroviral therapy (nanoART) in persistently infected macrophages. These findings are reviewed in the context of MLK3 biology and cellular signaling pathways relevant to new HIV-1 therapies. Graphical abstract.

KEYWORDS:

Autophagy; Central nervous system; Human immunodeficiency virus type 1; Macrophage; Mixed lineage kinase

PMID:
30617749
PMCID:
PMC6391203
[Available on 2020-03-01]
DOI:
10.1007/s11481-018-09829-8

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