Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 virus, is a major global health challenge, as there is no efficient treatment for the moderate to severe disease. ADP-ribosylation events are involved in regulating the life cycle of coronaviruses and the inflammatory reactions of the host, hence we assessed the repurposing of registered PARP inhibitors for the treatment of COVID-19. We detected high levels of oxidative stress and strong PARylation in all cell types in the lungs of COVID-19 patients. Interestingly, rucaparib, unlike other PARP inhibitors, reduced 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-induced overexpression of IL-6, a key cytokine in COVID-19, was inhibited by rucaparib at pharmacologically relevant concentrations. These findings build a case for repurposing rucaparib for treating COVID-19 disease.

Rucaparib was a generous gift from Clovis Oncology (Boulder, CO, USA). Clovis had no impact on study design and the conclusions drawn. Dr. Curtin is an inventor on patents WO 2005/012305 A2 and WO/2006/033006 with royalties paid to CRUK and Newcastle University, she gives her royalty share to charity and took no royalty in relation to this study. Other authors declare no conflict of interest.

The work was supported by grants from the NKFIH (K132623, K123975, K135150, K141142, TKP2021-EGA-10, TKP-2021-EGA-13, TKP2021-EGA-19, TKP2021-EGA-20, TKP2021-NVA-07). The Projects no. TKP2021-EGA-10, TKP-2021-EGA-13, TKP2021-EGA-19, TKP2021-EGA-20 were implemented with the support provided from the National Research, Development and Innovation Fund of Hungary, financed under the TKP2021-EGA funding scheme. Project no. TKP2021-NVA-07 has been implemented with the support provided from the National Research, Development and Innovation Fund of Hungary, financed under the TKP2021-NVA funding scheme. The POST-COVID2021-33 grant to PB was from the Hungarian Academy of Sciences. FAPESP grants 2018/18007-5 and 2020/05317-6 were to NH. The research was performed in collaboration with Cell and Tissue Culture Core Facility at the Szentagothai Research Centre of the University of Pecs. The work of D.B. was supported by the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences and the UNKP- 21-5 New National Excellence Program of the Ministry for Innovation and Technology. Prepared with the professional support of the Doctoral Student Scholarship Program of the Co-operative Doctoral Program of the Ministry of Innovation and Technology financed from the National Research, Development and Innovation Fund (to OM). The authors are grateful to Dr. Balazs Sarkadi (Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary) for his support and the critical revision of the manuscript.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics Committee of the University of Debrecen, Faculty of Medicine gave ethical approval for this work (6043/2022).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes