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Lookup NU author(s): Professor Nicola CurtinORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.Background and Purpose: To date, there are limited options for severe Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 virus. As ADP-ribosylation events are involved in regulating the life cycle of coronaviruses and the inflammatory reactions of the host; we have, here, assessed the repurposing of registered PARP inhibitors for the treatment of COVID-19. Experimental Approach: The effects of PARP inhibitors on virus uptake were assessed in cell-based experiments using multiple variants of SARS-CoV-2. The binding of rucaparib to spike protein was tested by molecular modelling and microcalorimetry. The anti-inflammatory properties of rucaparib were demonstrated in cell-based models upon challenging with recombinant spike protein or SARS-CoV-2 RNA vaccine. Key Results: We detected high levels of oxidative stress and strong PARylation in all cell types in the lungs of COVID-19 patients, both of which negatively correlated with lymphocytopaenia. Interestingly, rucaparib, unlike other tested PARP inhibitors, reduced the SARS-CoV-2 infection rate through binding to the conserved 493–498 amino acid region located in the spike-ACE2 interface in the spike protein and prevented viruses from binding to ACE2. In addition, the spike protein and viral RNA-induced overexpression of cytokines was down-regulated by the inhibition of PARP1 by rucaparib at pharmacologically relevant concentrations. Conclusion and Implications: These results point towards repurposing rucaparib for treating inflammatory responses in COVID-19.
Author(s): Papp H, Toth E, Bovari-Biri J, Banfai K, Juhasz P, Mahdi M, Russo LC, Bajusz D, Sipos A, Petri L, Szalai TV, Kemeny A, Madai M, Kuczmog A, Batta G, Mozner O, Vasko D, Hirsch E, Bohus P, Mehes G, Tozser J, Curtin NJ, Helyes Z, Toth A, Hoch NC, Jakab F, Keseru GM, Pongracz JE, Bai P
Publication type: Article
Publication status: Published
Journal: British Journal of Pharmacology
Year: 2024
Volume: 181
Issue: 23
Pages: 4782-4803
Print publication date: 01/12/2024
Online publication date: 27/08/2024
Acceptance date: 12/07/2024
Date deposited: 09/09/2024
ISSN (print): 0007-1188
ISSN (electronic): 1476-5381
Publisher: John Wiley and Sons Inc
URL: https://doi.org/10.1111/bph.17305
DOI: 10.1111/bph.17305
Data Access Statement: Primary data are available at https://figshare.com/s/6b25fd3d5de80ab3f51e (DOI: 10.6084/m9.figshare.19418957).
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