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

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Papp, Henrietta ; Toth, Emese ; Bovari-Biri, Judit ; Banfai, Krisztina ; Juhasz, Peter ; Mahdi, Mohamed ; Russo, Lilian Cristina ; Bajusz, David ; Sipos, Adrienn ; Petri, Laszlo ; Szalai, Tibor Viktor ; Kemeny, Agnes ; Madai, Monika ; Kuczmog, Anett ; Batta, Gyula ; Mozner, Orsolya ; Vasko, Dorottya ; Hirsch, Edit ; Bohus, Peter ; Mehes, Gabor ; Tozser, Jozsef ; Curtin, Nicola J. ; Helyes, Zsuzsanna ; Toth, Attila ; Hoch, Nicolas C. ; Jakab, Ferenc ; Keseru, Gyorgy M. ; Pongracz, Judit E. ; Bai, Peter

• Document type: Journal article
• Source: British Journal of Pharmacology; v. 181, n. 23, p. 22-pg., 2024-08-27.

Abstract

Background and PurposeTo 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 ApproachThe 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 ResultsWe 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 ImplicationsThese results point towards repurposing rucaparib for treating inflammatory responses in COVID-19. image (AU)

• FAPESP's process: 20/05317-6 - Inhibition of the viral macrodomain as a strategy for Coronavirus treatment
• Grantee: Nicolas Carlos Hoch
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/18007-5 - Protein ADP-ribosylation: DNA damage signalling and impacts on human health
• Grantee: Nicolas Carlos Hoch
• Support Opportunities: Research Grants - Young Investigators Grants