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Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity

Fowler, Benjamin J., Gelfand, Bradley D., Kim, Younghee, Kerur, Nagaraj, Tarallo, Valeria, Hirano, Yoshio, Amarnath, Shoba, Fowler, Daniel H., Radwan, Marta, Young, Mark Thomas, Pittman, Keir, Kubes, Paul, Agarwal, Hitesh K., Parang, Keykavous, Hinton, David R., Bastos-Carvalho, Ana, Li, Shengjian, Yasuma, Tetsuhiro, Mizutani, Takeshi, Yasuma, Reo, Wright, Charles and Ambati, Jayakrishna 2014. Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity. Science 346 (6212) , pp. 1000-1003. 10.1126/science.1261754

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Abstract

Nucleoside reverse transcriptase inhibitors (NRTIs) are mainstay therapeutics for HIV that block retrovirus replication. Alu (an endogenous retroelement that also requires reverse transcriptase for its life cycle)–derived RNAs activate P2X7 and the NLRP3 inflammasome to cause cell death of the retinal pigment epithelium in geographic atrophy, a type of age-related macular degeneration. We found that NRTIs inhibit P2X7-mediated NLRP3 inflammasome activation independent of reverse transcriptase inhibition. Multiple approved and clinically relevant NRTIs prevented caspase-1 activation, the effector of the NLRP3 inflammasome, induced by Alu RNA. NRTIs were efficacious in mouse models of geographic atrophy, choroidal neovascularization, graft-versus-host disease, and sterile liver inflammation. Our findings suggest that NRTIs are ripe for drug repurposing in P2X7-driven diseases.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Subjects: Q Science > QH Natural history > QH301 Biology
R Medicine > RM Therapeutics. Pharmacology
Publisher: American Association for the Advancement of Science
ISSN: 0036-8075
Funders: BBSRC
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 24 October 2014
Last Modified: 28 Jun 2019 05:35
URI: http://orca.cf.ac.uk/id/eprint/67732

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