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Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
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Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity
Benjamin J Fowler1, Bradley D Gelfand2, Younghee Kim3
1Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA. Department of Physiology, University of Kentucky, Lexington, KY 40536, USA.
Science (New York, N.Y.)
|November 22, 2014
Summary
Nucleoside reverse transcriptase inhibitors (NRTIs) repurposed for P2X7-driven diseases. These HIV drugs inhibit inflammasome activation, showing efficacy in models of geographic atrophy and inflammation.
Area of Science:
- Immunology
- Virology
- Ophthalmology
Background:
- Nucleoside reverse transcriptase inhibitors (NRTIs) are critical HIV treatments that inhibit viral replication.
- Alu RNA activates P2X7 and NLRP3 inflammasome, leading to retinal cell death in geographic atrophy, a form of age-related macular degeneration.
Purpose of the Study:
- To investigate the potential of NRTIs in treating P2X7-driven inflammatory diseases.
- To determine if NRTIs can inhibit NLRP3 inflammasome activation independent of their antiviral activity.
Main Methods:
- Assessed NRTI inhibition of P2X7-mediated NLRP3 inflammasome activation induced by Alu RNA.
- Evaluated caspase-1 activation as a readout for inflammasome activity.
- Tested NRTI efficacy in mouse models of geographic atrophy, choroidal neovascularization, graft-versus-host disease, and sterile liver inflammation.
Main Results:
- NRTIs effectively inhibited P2X7-mediated NLRP3 inflammasome activation and caspase-1 cleavage induced by Alu RNA.
- This inhibition occurred independently of reverse transcriptase inhibition.
- NRTIs demonstrated therapeutic effects in multiple preclinical models of inflammatory diseases.
Conclusions:
- NRTIs possess potent anti-inflammatory properties by inhibiting the P2X7-NLRP3 inflammasome pathway.
- Drug repurposing of NRTIs is a promising strategy for treating P2X7-driven inflammatory conditions, including geographic atrophy.
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