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Related Experiment Video

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High-throughput Screening for Broad-spectrum Chemical Inhibitors of RNA Viruses
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Broad Spectrum Mixed Lineage Kinase Type 3 Inhibition and HIV-1 Persistence in Macrophages.

Priyanka Saminathan1, Bhavesh D Kevadiya2, Daniel F Marker3

  • 1Center for Neurotherapeutics Discovery and Department of Microbiology & Immunology, University of Rochester Medical Center, Rochester, NY, USA.

Journal of Neuroimmune Pharmacology : the Official Journal of the Society on Neuroimmune Pharmacology
|January 9, 2019
PubMed
Summary

Mixed lineage kinase (MLK) inhibitors, like URMC-099, show promise for treating HIV-1-associated neurocognitive disorders (HAND). This compound reverses synaptic damage and restores protective autophagy when combined with nanoformulated antiretroviral therapy (nanoART).

Keywords:
AutophagyCentral nervous systemHuman immunodeficiency virus type 1MacrophageMixed lineage kinase

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Area of Science:

  • Neuroscience
  • Immunology
  • Pharmacology

Background:

  • Mixed lineage kinases (MLKs) mediate oxidative stress and inflammation in innate immune cells.
  • Human immunodeficiency virus type 1 (HIV-1) infection exacerbates these conditions, contributing to HIV-1-associated neurocognitive disorders (HAND).

Purpose of the Study:

  • To identify novel therapeutic strategies for HAND by developing broad-spectrum MLK inhibitors.
  • To evaluate the efficacy of lead compound URMC-099 in preclinical models of HAND and HIV-1 infection.

Main Methods:

  • Creation of a drug-like MLK inhibitor library.
  • Assessment of URMC-099's effects on synaptic architecture in HAND models.
  • Evaluation of URMC-099 in combination with nanoformulated antiretroviral therapy (nanoART) in HIV-1 infected macrophages.

Main Results:

  • The lead compound URMC-099 reversed synaptic damage in models of HAND.
  • URMC-099 restored autophagy, a protective cellular response, when administered with nanoART in persistently infected macrophages.

Conclusions:

  • MLK inhibitors, exemplified by URMC-099, represent a promising therapeutic avenue for HAND.
  • Combined treatment with URMC-099 and nanoART may offer a novel strategy to combat HIV-1 neuropathogenesis by modulating MLK signaling and autophagy.