The PARP inhibitor rucaparib blocks SARS-CoV-2 virus binding to cells and the immune reaction in models of COVID-19

Papp, Henrietta and Tóth, Emese and Bovári-Biri, Judit and Bánfai, Krisztina and Juhász, Péter and Mahdi, M. and Russo, L.C. and Bajusz, Dávid and Sipos, Adrienn and Petri, László and Szalai, Tibor Viktor and Kemény, Ágnes and Madai, Mónika and Kuczmog, Anett and Batta, Gyula and Mózner, Orsolya and Vaskó, Dorottya and Hirsch, Edit and Bohus, P. and Méhes, Gábor and Tőzsér, József and Curtin, N.J. and Helyes, Zsuzsanna and Tóth, A. and Hoch, N.C. and Jakab, Ferenc and Keserű, György Miklós and Pongrácz, Judit and Bay, Péter (2024) The PARP inhibitor rucaparib blocks SARS-CoV-2 virus binding to cells and the immune reaction in models of COVID-19. BRITISH JOURNAL OF PHARMACOLOGY. ISSN 0007-1188

Preview

Text 2024_BritishJPharmacology-Papp-ThePARPinhibitorrucaparibblocksSARSCoV2virusbindingtocellsandtheimmune.pdf - Published Version Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (10MB) | Preview

Abstract

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. © 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Actions (login required)

Edit Item