tetano
Editor, Senior Moderator
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[SUP] 1 2 3 [/SUP], Emese Tóth[SUP] 4 5 [/SUP], Judit Bóvári-Biri[SUP] 3 6 [/SUP], Krisztina Bánfai[SUP] 3 6 [/SUP], Péter Juhász[SUP] 7 [/SUP], Mohamed Mahdi[SUP] 8 [/SUP], Lilian Cristina Russo[SUP] 9 [/SUP], Dávid Bajusz[SUP] 10 [/SUP], Adrienn Sipos[SUP] 4 5 [/SUP], László Petri[SUP] 10 [/SUP], Tibor Viktor Szalai[SUP] 10 11 [/SUP], Ágnes Kemény[SUP] 3 12 13 [/SUP], Mónika Madai[SUP] 1 2 3 [/SUP], Anett Kuczmog[SUP] 1 2 3 [/SUP], Gyula Batta[SUP] 14 [/SUP], Orsolya Mózner[SUP] 15 16 [/SUP], Dorottya Vaskó[SUP] 17 [/SUP], Edit Hirsch[SUP] 17 [/SUP], Péter Bohus[SUP] 18 [/SUP], Gábor Méhes[SUP] 7 [/SUP], József Tőzsér[SUP] 8 [/SUP], Nicola J Curtin[SUP] 19 [/SUP], Zsuzsanna Helyes[SUP] 12 20 21 [/SUP], Attila Tóth[SUP] 22 [/SUP], Nicolas C Hoch[SUP] 9 [/SUP], Ferenc Jakab[SUP] 1 2 [/SUP], György M Keserű[SUP] 10 17 [/SUP], Judit E Pongrácz[SUP] 3 6 [/SUP], Péter Bai[SUP] 3 4 23 24 [/SUP]
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[SUP] 1 2 3 [/SUP], Emese Tóth[SUP] 4 5 [/SUP], Judit Bóvári-Biri[SUP] 3 6 [/SUP], Krisztina Bánfai[SUP] 3 6 [/SUP], Péter Juhász[SUP] 7 [/SUP], Mohamed Mahdi[SUP] 8 [/SUP], Lilian Cristina Russo[SUP] 9 [/SUP], Dávid Bajusz[SUP] 10 [/SUP], Adrienn Sipos[SUP] 4 5 [/SUP], László Petri[SUP] 10 [/SUP], Tibor Viktor Szalai[SUP] 10 11 [/SUP], Ágnes Kemény[SUP] 3 12 13 [/SUP], Mónika Madai[SUP] 1 2 3 [/SUP], Anett Kuczmog[SUP] 1 2 3 [/SUP], Gyula Batta[SUP] 14 [/SUP], Orsolya Mózner[SUP] 15 16 [/SUP], Dorottya Vaskó[SUP] 17 [/SUP], Edit Hirsch[SUP] 17 [/SUP], Péter Bohus[SUP] 18 [/SUP], Gábor Méhes[SUP] 7 [/SUP], József Tőzsér[SUP] 8 [/SUP], Nicola J Curtin[SUP] 19 [/SUP], Zsuzsanna Helyes[SUP] 12 20 21 [/SUP], Attila Tóth[SUP] 22 [/SUP], Nicolas C Hoch[SUP] 9 [/SUP], Ferenc Jakab[SUP] 1 2 [/SUP], György M Keserű[SUP] 10 17 [/SUP], Judit E Pongrácz[SUP] 3 6 [/SUP], Péter Bai[SUP] 3 4 23 24 [/SUP]
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.