Synergistic Antiviral Activity of Pamapimod and Pioglitazone against SARS-CoV-2 and Its Variants of Concern
The SARS-CoV-2 pandemic remains a major public health threat, especially due to newly emerging SARS-CoV-2 Variants of Concern (VoCs), which are more efficiently transmitted, more virulent, and more able to escape naturally acquired and vaccine-induced immunity. Recently, the protease inhibitor Paxlo...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-06-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/12/6830 |
| _version_ | 1797486403475472384 |
|---|---|
| author | Christian Setz Maximilian Große Janina Auth Maria Fröba Pia Rauch Alexander Bausch Matthew Wright Ulrich Schubert |
| author_facet | Christian Setz Maximilian Große Janina Auth Maria Fröba Pia Rauch Alexander Bausch Matthew Wright Ulrich Schubert |
| author_sort | Christian Setz |
| collection | DOAJ |
| description | The SARS-CoV-2 pandemic remains a major public health threat, especially due to newly emerging SARS-CoV-2 Variants of Concern (VoCs), which are more efficiently transmitted, more virulent, and more able to escape naturally acquired and vaccine-induced immunity. Recently, the protease inhibitor Paxlovid<sup>®</sup> and the polymerase inhibitor molnupiravir, both targeting mutant-prone viral components, were approved for high-risk COVID-19 patients. Nevertheless, effective therapeutics to treat COVID-19 are urgently needed, especially small molecules acting independently of VoCs and targeting genetically stable cellular pathways which are crucial for viral replication. Pamapimod is a selective inhibitor of p38 Mitogen-Activated Protein Kinase alpha (p38 MAPKα) that has been extensively clinically evaluated for the treatment of rheumatoid arthritis. Signaling via p38 has recently been described as a key pathway for the replication of SARS-CoV-2. Here, we reveal that the combination of pamapimod with pioglitazone, an anti-inflammatory and approved drug for the treatment of type 2 diabetes, possesses potent and synergistic activity to inhibit SARS-CoV-2 replication in vitro. Both drugs showed similar antiviral potency across several cultured cell types and similar antiviral activity against SARS-CoV-2 Wuhan type, and the VoCs Alpha, Beta, Gamma, Delta, and Omicron. These data support the combination of pamapimod and pioglitazone as a potential therapy to reduce duration and severity of disease in COVID-19 patients, an assumption currently evaluated in an ongoing phase II clinical study. |
| first_indexed | 2024-03-09T23:32:43Z |
| format | Article |
| id | doaj.art-fa9a4435104f4b6ca55672aad04dd91e |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T23:32:43Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-fa9a4435104f4b6ca55672aad04dd91e2023-11-23T17:07:32ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-06-012312683010.3390/ijms23126830Synergistic Antiviral Activity of Pamapimod and Pioglitazone against SARS-CoV-2 and Its Variants of ConcernChristian Setz0Maximilian Große1Janina Auth2Maria Fröba3Pia Rauch4Alexander Bausch5Matthew Wright6Ulrich Schubert7Institute of Virology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, GermanyInstitute of Virology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, GermanyInstitute of Virology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, GermanyInstitute of Virology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, GermanyInstitute of Virology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, GermanyKinarus Therapeutics AG, 4057 Basel, SwitzerlandKinarus Therapeutics AG, 4057 Basel, SwitzerlandInstitute of Virology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, GermanyThe SARS-CoV-2 pandemic remains a major public health threat, especially due to newly emerging SARS-CoV-2 Variants of Concern (VoCs), which are more efficiently transmitted, more virulent, and more able to escape naturally acquired and vaccine-induced immunity. Recently, the protease inhibitor Paxlovid<sup>®</sup> and the polymerase inhibitor molnupiravir, both targeting mutant-prone viral components, were approved for high-risk COVID-19 patients. Nevertheless, effective therapeutics to treat COVID-19 are urgently needed, especially small molecules acting independently of VoCs and targeting genetically stable cellular pathways which are crucial for viral replication. Pamapimod is a selective inhibitor of p38 Mitogen-Activated Protein Kinase alpha (p38 MAPKα) that has been extensively clinically evaluated for the treatment of rheumatoid arthritis. Signaling via p38 has recently been described as a key pathway for the replication of SARS-CoV-2. Here, we reveal that the combination of pamapimod with pioglitazone, an anti-inflammatory and approved drug for the treatment of type 2 diabetes, possesses potent and synergistic activity to inhibit SARS-CoV-2 replication in vitro. Both drugs showed similar antiviral potency across several cultured cell types and similar antiviral activity against SARS-CoV-2 Wuhan type, and the VoCs Alpha, Beta, Gamma, Delta, and Omicron. These data support the combination of pamapimod and pioglitazone as a potential therapy to reduce duration and severity of disease in COVID-19 patients, an assumption currently evaluated in an ongoing phase II clinical study.https://www.mdpi.com/1422-0067/23/12/6830COVID-19SARS-CoV-2coronavirusvariants of concernvirus variantspioglitazone |
| spellingShingle | Christian Setz Maximilian Große Janina Auth Maria Fröba Pia Rauch Alexander Bausch Matthew Wright Ulrich Schubert Synergistic Antiviral Activity of Pamapimod and Pioglitazone against SARS-CoV-2 and Its Variants of Concern International Journal of Molecular Sciences COVID-19 SARS-CoV-2 coronavirus variants of concern virus variants pioglitazone |
| title | Synergistic Antiviral Activity of Pamapimod and Pioglitazone against SARS-CoV-2 and Its Variants of Concern |
| title_full | Synergistic Antiviral Activity of Pamapimod and Pioglitazone against SARS-CoV-2 and Its Variants of Concern |
| title_fullStr | Synergistic Antiviral Activity of Pamapimod and Pioglitazone against SARS-CoV-2 and Its Variants of Concern |
| title_full_unstemmed | Synergistic Antiviral Activity of Pamapimod and Pioglitazone against SARS-CoV-2 and Its Variants of Concern |
| title_short | Synergistic Antiviral Activity of Pamapimod and Pioglitazone against SARS-CoV-2 and Its Variants of Concern |
| title_sort | synergistic antiviral activity of pamapimod and pioglitazone against sars cov 2 and its variants of concern |
| topic | COVID-19 SARS-CoV-2 coronavirus variants of concern virus variants pioglitazone |
| url | https://www.mdpi.com/1422-0067/23/12/6830 |
| work_keys_str_mv | AT christiansetz synergisticantiviralactivityofpamapimodandpioglitazoneagainstsarscov2anditsvariantsofconcern AT maximiliangroße synergisticantiviralactivityofpamapimodandpioglitazoneagainstsarscov2anditsvariantsofconcern AT janinaauth synergisticantiviralactivityofpamapimodandpioglitazoneagainstsarscov2anditsvariantsofconcern AT mariafroba synergisticantiviralactivityofpamapimodandpioglitazoneagainstsarscov2anditsvariantsofconcern AT piarauch synergisticantiviralactivityofpamapimodandpioglitazoneagainstsarscov2anditsvariantsofconcern AT alexanderbausch synergisticantiviralactivityofpamapimodandpioglitazoneagainstsarscov2anditsvariantsofconcern AT matthewwright synergisticantiviralactivityofpamapimodandpioglitazoneagainstsarscov2anditsvariantsofconcern AT ulrichschubert synergisticantiviralactivityofpamapimodandpioglitazoneagainstsarscov2anditsvariantsofconcern |