Non-Catalytic Inhibitors of the p38/MK2 Interface: Repurposing Approved Drugs to Target Neuroinflammation in
Maylynn Hu1, Andrew Li1, Payton Fleming1
1Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Emory University, Atlanta, Georgia 30322, United States.
Abstract:
Neuroinflammation is a key driver of Alzheimer's disease and an emerging therapeutic target. The p38/MK2 pathway regulates microglial cytokine production, yet previous attempts have not yielded modulators with clinically suitable properties. Here, we apply an integrative structure-guided and screening strategy to identify small-molecule disruptors of the p38/MK2 protein-protein interaction (PPI). Virtual screening of FDA-approved drugs prioritized nilotinib, a BCR-ABL inhibitor, as a putative PPI disruptor. Biochemical and molecular dynamics analyses confirmed that nilotinib binds to p38, blocks MK2 association, and suppresses cytokine release in microglia. Guided by these findings, we developed a lysate-based TR-FRET ultrahigh-throughput assay that identified additional inhibitors, including α1-adrenergic antagonists doxazosin, terazosin, and alfuzosin. These compounds suppressed cytokine induction via docking groove blockade. Together, these results establish a non-ATP-competitive approach for selectively targeting the p38/MK2 complex and highlight the translational potential of drug repurposing to modulate neuroinflammation in Alzheimer's disease.
Insights
Researchers identified existing drugs, like nilotinib and alpha-1 adrenergic antagonists, that can disrupt the p38/MK2 pathway. This offers a new strategy for targeting neuroinflammation in Alzheimer's disease.
Area of Science:
- Neuroscience
- Pharmacology
- Drug Discovery
Background:
- Neuroinflammation is a critical factor in Alzheimer's disease pathogenesis.
- The p38/MK2 pathway is a key regulator of microglial cytokine production, but lacks effective modulators.
- Targeting protein-protein interactions (PPIs) offers a promising therapeutic avenue.
Purpose of the Study:
- To identify small molecules that disrupt the p38/MK2 protein-protein interaction.
- To explore drug repurposing for targeting neuroinflammation in Alzheimer's disease.
Main Methods:
- Integrative structure-guided design and screening strategy.
- Virtual screening of FDA-approved drugs.
- Biochemical assays and molecular dynamics simulations.
- Development of a TR-FRET ultrahigh-throughput assay.
- Docking groove blockade analysis.
Main Results:
- Nilotinib, a BCR-ABL inhibitor, was identified as a p38/MK2 PPI disruptor.
- Nilotinib suppresses microglial cytokine release by blocking MK2 association with p38.
- Alpha-1 adrenergic antagonists (doxazosin, terazosin, alfuzosin) were identified as novel inhibitors.
- These compounds act via docking groove blockade to inhibit cytokine induction.
Conclusions:
- A non-ATP-competitive strategy for targeting the p38/MK2 complex was established.
- Drug repurposing holds significant translational potential for Alzheimer's disease neuroinflammation.
- Novel small molecules effectively modulate microglial activation pathways.
Related Concept Videos
01:22Alzheimer's Disease: Treatment
01:26Alzheimer's Disease: Overview
The clinical diagnosis of AD hinges on the presence of memory and other cognitive impairments. Biomarkers, such as changes in Aβ...
01:30Cognitive Enhancers: Cholinesterase Inhibitors and NMDA Receptor Antagonists