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Updated: Jan 31, 2026
High-throughput Screening for Broad-spectrum Chemical Inhibitors of RNA Viruses
Published on: May 5, 2014
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.
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.
Insights
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).
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.
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