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Br J Pharmacol
. 2024 Aug 27.
doi: 10.1111/bph.17305. Online ahead of print. The PARP inhibitor rucaparib blocks SARS-CoV-2 virus binding to cells and the immune reaction in models of COVID-19
Henrietta Papp 1 2 3 , Emese Tóth 4 5 , Judit Bóvári-Biri 3 6 , Krisztina Bánfai 3 6 , Péter Juhász 7 , Mohamed Mahdi 8 , Lilian Cristina Russo 9 , Dávid Bajusz 10 , Adrienn Sipos 4 5 , László Petri 10 , Tibor Viktor Szalai 10 11 , Ágnes Kemény 3 12 13 , Mónika Madai 1 2 3 , Anett Kuczmog 1 2 3 , Gyula Batta 14 , Orsolya Mózner 15 16 , Dorottya Vaskó 17 , Edit Hirsch 17 , Péter Bohus 18 , Gábor Méhes 7 , József Tőzsér 8 , Nicola J Curtin 19 , Zsuzsanna Helyes 12 20 21 , Attila Tóth 22 , Nicolas C Hoch 9 , Ferenc Jakab 1 2 , György M Keserű 10 17 , Judit E Pongrácz 3 6 , Péter Bai 3 4 23 24
Affiliations
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.
Keywords: ACE2; COVID‐19; NFκB; SARS‐COV‐2 spike protein; SARS‐CoV‐2 RNA; rucaparib; viral lung inflammation.
. 2024 Aug 27.
doi: 10.1111/bph.17305. Online ahead of print. The PARP inhibitor rucaparib blocks SARS-CoV-2 virus binding to cells and the immune reaction in models of COVID-19
Henrietta Papp 1 2 3 , Emese Tóth 4 5 , Judit Bóvári-Biri 3 6 , Krisztina Bánfai 3 6 , Péter Juhász 7 , Mohamed Mahdi 8 , Lilian Cristina Russo 9 , Dávid Bajusz 10 , Adrienn Sipos 4 5 , László Petri 10 , Tibor Viktor Szalai 10 11 , Ágnes Kemény 3 12 13 , Mónika Madai 1 2 3 , Anett Kuczmog 1 2 3 , Gyula Batta 14 , Orsolya Mózner 15 16 , Dorottya Vaskó 17 , Edit Hirsch 17 , Péter Bohus 18 , Gábor Méhes 7 , József Tőzsér 8 , Nicola J Curtin 19 , Zsuzsanna Helyes 12 20 21 , Attila Tóth 22 , Nicolas C Hoch 9 , Ferenc Jakab 1 2 , György M Keserű 10 17 , Judit E Pongrácz 3 6 , Péter Bai 3 4 23 24
Affiliations
- PMID: 39191429
- DOI: 10.1111/bph.17305
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.
Keywords: ACE2; COVID‐19; NFκB; SARS‐COV‐2 spike protein; SARS‐CoV‐2 RNA; rucaparib; viral lung inflammation.