Repurposing Drugs for Synergistic Combination Therapies to Counteract Monkeypox Virus Tecovirimat Resistance
The ongoing monkeypox (mpox) disease outbreak has spread to multiple countries in Central Africa and evidence indicates it is driven by a more virulent clade I monkeypox virus (MPXV) strain than the clade II strain associated with the 2022 global mpox outbreak, which led the WHO to declare this mpox...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-01-01
|
| Series: | Viruses |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4915/17/1/92 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832587320607375360 |
|---|---|
| author | Haydar Witwit Beatrice Cubitt Roaa Khafaji Esteban M. Castro Miguel Goicoechea Maria M. Lorenzo Rafael Blasco Luis Martinez-Sobrido Juan C. de la Torre |
| author_facet | Haydar Witwit Beatrice Cubitt Roaa Khafaji Esteban M. Castro Miguel Goicoechea Maria M. Lorenzo Rafael Blasco Luis Martinez-Sobrido Juan C. de la Torre |
| author_sort | Haydar Witwit |
| collection | DOAJ |
| description | The ongoing monkeypox (mpox) disease outbreak has spread to multiple countries in Central Africa and evidence indicates it is driven by a more virulent clade I monkeypox virus (MPXV) strain than the clade II strain associated with the 2022 global mpox outbreak, which led the WHO to declare this mpox outbreak a public health emergency of international concern. The FDA-approved small molecule antiviral tecovirimat (TPOXX) is recommended to treat mpox cases with severe symptoms, but the limited efficacy of TPOXX and the emergence of TPOXX resistant MPXV variants has challenged this medical practice of care and highlighted the urgent need for alternative therapeutic strategies. In this study we have used vaccinia virus (VACV) as a surrogate of MPXV to assess the antiviral efficacy of combination therapy of TPOXX together with mycophenolate mofetil (MMF), an FDA-approved immunosuppressive agent that we have shown to inhibit VACV and MPXV, or the N-myristoyltransferase (NMT) inhibitor IMP-1088. Both MMF and IMP-1088 drugs exhibited strong dose-dependent antiviral activity against VACV and mpox, and potent synergistic effects in conjunction with TPOXX. Our findings support combination therapy of direct-acting (TPOXX) and host-targeted (MMF and IMP-1088) antivirals as a promising approach to treat mpox and prevent the emergence and spread of TPOXX-resistant MPXV variants. |
| format | Article |
| id | doaj-art-d94d8a379ad04e08ac8c11fe623a45fe |
| institution | Kabale University |
| issn | 1999-4915 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj-art-d94d8a379ad04e08ac8c11fe623a45fe2025-01-24T13:52:34ZengMDPI AGViruses1999-49152025-01-011719210.3390/v17010092Repurposing Drugs for Synergistic Combination Therapies to Counteract Monkeypox Virus Tecovirimat ResistanceHaydar Witwit0Beatrice Cubitt1Roaa Khafaji2Esteban M. Castro3Miguel Goicoechea4Maria M. Lorenzo5Rafael Blasco6Luis Martinez-Sobrido7Juan C. de la Torre8Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USADepartment of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USADepartment of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USATexas Biomedical Research Institute, San Antonio, TX 78227, USADivision of Infectious Diseases, Scripps Health, San Diego, CA 92103, USADepartamento de Biotecnología, INIA CSIC, 28040 Madrid, SpainDepartamento de Biotecnología, INIA CSIC, 28040 Madrid, SpainTexas Biomedical Research Institute, San Antonio, TX 78227, USADepartment of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USAThe ongoing monkeypox (mpox) disease outbreak has spread to multiple countries in Central Africa and evidence indicates it is driven by a more virulent clade I monkeypox virus (MPXV) strain than the clade II strain associated with the 2022 global mpox outbreak, which led the WHO to declare this mpox outbreak a public health emergency of international concern. The FDA-approved small molecule antiviral tecovirimat (TPOXX) is recommended to treat mpox cases with severe symptoms, but the limited efficacy of TPOXX and the emergence of TPOXX resistant MPXV variants has challenged this medical practice of care and highlighted the urgent need for alternative therapeutic strategies. In this study we have used vaccinia virus (VACV) as a surrogate of MPXV to assess the antiviral efficacy of combination therapy of TPOXX together with mycophenolate mofetil (MMF), an FDA-approved immunosuppressive agent that we have shown to inhibit VACV and MPXV, or the N-myristoyltransferase (NMT) inhibitor IMP-1088. Both MMF and IMP-1088 drugs exhibited strong dose-dependent antiviral activity against VACV and mpox, and potent synergistic effects in conjunction with TPOXX. Our findings support combination therapy of direct-acting (TPOXX) and host-targeted (MMF and IMP-1088) antivirals as a promising approach to treat mpox and prevent the emergence and spread of TPOXX-resistant MPXV variants.https://www.mdpi.com/1999-4915/17/1/92monkeypoxantiviralmpoxdrug synergistic interactions<i>Poxviridae</i>VACV |
| spellingShingle | Haydar Witwit Beatrice Cubitt Roaa Khafaji Esteban M. Castro Miguel Goicoechea Maria M. Lorenzo Rafael Blasco Luis Martinez-Sobrido Juan C. de la Torre Repurposing Drugs for Synergistic Combination Therapies to Counteract Monkeypox Virus Tecovirimat Resistance Viruses monkeypox antiviral mpox drug synergistic interactions <i>Poxviridae</i> VACV |
| title | Repurposing Drugs for Synergistic Combination Therapies to Counteract Monkeypox Virus Tecovirimat Resistance |
| title_full | Repurposing Drugs for Synergistic Combination Therapies to Counteract Monkeypox Virus Tecovirimat Resistance |
| title_fullStr | Repurposing Drugs for Synergistic Combination Therapies to Counteract Monkeypox Virus Tecovirimat Resistance |
| title_full_unstemmed | Repurposing Drugs for Synergistic Combination Therapies to Counteract Monkeypox Virus Tecovirimat Resistance |
| title_short | Repurposing Drugs for Synergistic Combination Therapies to Counteract Monkeypox Virus Tecovirimat Resistance |
| title_sort | repurposing drugs for synergistic combination therapies to counteract monkeypox virus tecovirimat resistance |
| topic | monkeypox antiviral mpox drug synergistic interactions <i>Poxviridae</i> VACV |
| url | https://www.mdpi.com/1999-4915/17/1/92 |
| work_keys_str_mv | AT haydarwitwit repurposingdrugsforsynergisticcombinationtherapiestocounteractmonkeypoxvirustecovirimatresistance AT beatricecubitt repurposingdrugsforsynergisticcombinationtherapiestocounteractmonkeypoxvirustecovirimatresistance AT roaakhafaji repurposingdrugsforsynergisticcombinationtherapiestocounteractmonkeypoxvirustecovirimatresistance AT estebanmcastro repurposingdrugsforsynergisticcombinationtherapiestocounteractmonkeypoxvirustecovirimatresistance AT miguelgoicoechea repurposingdrugsforsynergisticcombinationtherapiestocounteractmonkeypoxvirustecovirimatresistance AT mariamlorenzo repurposingdrugsforsynergisticcombinationtherapiestocounteractmonkeypoxvirustecovirimatresistance AT rafaelblasco repurposingdrugsforsynergisticcombinationtherapiestocounteractmonkeypoxvirustecovirimatresistance AT luismartinezsobrido repurposingdrugsforsynergisticcombinationtherapiestocounteractmonkeypoxvirustecovirimatresistance AT juancdelatorre repurposingdrugsforsynergisticcombinationtherapiestocounteractmonkeypoxvirustecovirimatresistance |