Henrietta Papp, Emese Tóth, Judit Bóvári-Biri, Krisztina Bánfai, Péter Juhász, Mohamed Mahdi, Lilian Cristina Russo, Dávid Bajusz, Adrienn Sipos, László Petri, Tibor Viktor Szalai, Ágnes Kemény, Mónika Madai, Anett Kuczmog, Gyula Batta, Orsolya Mózner, Dorottya Vaskó, Edit Hirsch, Péter Bohus, Gábor Méhes, József Tőzsér, Nicola J. Curtin, Zsuzsanna Helyes, Attila Tóth, Nicolas C. Hoch, Ferenc Jakab, György M. Keserű, Judit E. Pongrácz, Péter Bai
{"title":"在 COVID-19 模型中，PARP 抑制剂 rucaparib 阻止了 SARS-CoV-2 病毒与细胞的结合以及免疫反应。","authors":"Henrietta Papp, Emese Tóth, Judit Bóvári-Biri, Krisztina Bánfai, Péter Juhász, Mohamed Mahdi, Lilian Cristina Russo, Dávid Bajusz, Adrienn Sipos, László Petri, Tibor Viktor Szalai, Ágnes Kemény, Mónika Madai, Anett Kuczmog, Gyula Batta, Orsolya Mózner, Dorottya Vaskó, Edit Hirsch, Péter Bohus, Gábor Méhes, József Tőzsér, Nicola J. Curtin, Zsuzsanna Helyes, Attila Tóth, Nicolas C. Hoch, Ferenc Jakab, György M. Keserű, Judit E. Pongrácz, Péter Bai","doi":"10.1111/bph.17305","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background and Purpose</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> Experimental Approach</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> Key Results</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> Conclusion and Implications</h3>\n \n <p>These results point towards repurposing rucaparib for treating inflammatory responses in COVID-19.</p>\n </section>\n </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8000,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17305","citationCount":"0","resultStr":"{\"title\":\"The PARP inhibitor rucaparib blocks SARS-CoV-2 virus binding to cells and the immune reaction in models of COVID-19\",\"authors\":\"Henrietta Papp, Emese Tóth, Judit Bóvári-Biri, Krisztina Bánfai, Péter Juhász, Mohamed Mahdi, Lilian Cristina Russo, Dávid Bajusz, Adrienn Sipos, László Petri, Tibor Viktor Szalai, Ágnes Kemény, Mónika Madai, Anett Kuczmog, Gyula Batta, Orsolya Mózner, Dorottya Vaskó, Edit Hirsch, Péter Bohus, Gábor Méhes, József Tőzsér, Nicola J. 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The PARP inhibitor rucaparib blocks SARS-CoV-2 virus binding to cells and the immune reaction in models of COVID-19
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.
期刊介绍：
The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries.
Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues.
In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
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