Identification of In Vitro Inhibitors of Monkeypox Replication
ABSTRACT Monkeypox virus (MPXV) infections in humans have historically been restricted to regions of endemicity in Africa. However, in 2022, an alarming number of MPXV cases were reported globally, with evidence of person-to-person transmission. Because of this, the World Health Organization (WHO) d...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2023-08-01
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| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.04745-22 |
| _version_ | 1797741766598721536 |
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| author | Kevin Chiem Aitor Nogales Maria Lorenzo Desarey Morales Vasquez Yan Xiang Yogesh K. Gupta Rafael Blasco Juan Carlos de la Torre Luis Martínez-Sobrido |
| author_facet | Kevin Chiem Aitor Nogales Maria Lorenzo Desarey Morales Vasquez Yan Xiang Yogesh K. Gupta Rafael Blasco Juan Carlos de la Torre Luis Martínez-Sobrido |
| author_sort | Kevin Chiem |
| collection | DOAJ |
| description | ABSTRACT Monkeypox virus (MPXV) infections in humans have historically been restricted to regions of endemicity in Africa. However, in 2022, an alarming number of MPXV cases were reported globally, with evidence of person-to-person transmission. Because of this, the World Health Organization (WHO) declared the MPXV outbreak a public health emergency of international concern. The supply of MPXV vaccines is limited, and only two antivirals, tecovirimat and brincidofovir, approved by the U.S. Food and Drug Administration (FDA) for the treatment of smallpox, are currently available for the treatment of MPXV infection. Here, we evaluated 19 compounds previously shown to inhibit different RNA viruses for their ability to inhibit orthopoxvirus infections. We first used recombinant vaccinia virus (rVACV) expressing fluorescence (mScarlet or green fluorescent protein [GFP]) and luciferase (Nluc) reporter genes to identify compounds with antiorthopoxvirus activity. Seven compounds from the ReFRAME library (antimycin A, mycophenolic acid, AVN-944, pyrazofurin, mycophenolate mofetil, azaribine, and brequinar) and six compounds from the NPC library (buparvaquone, valinomycin, narasin, monensin, rotenone, and mubritinib) showed inhibitory activity against rVACV. Notably, the anti-VACV activity of some of the compounds in the ReFRAME library (antimycin A, mycophenolic acid, AVN-944, mycophenolate mofetil, and brequinar) and all the compounds from the NPC library (buparvaquone, valinomycin, narasin, monensin, rotenone, and mubritinib) were confirmed with MPXV, demonstrating their inhibitory activity in vitro against two orthopoxviruses. IMPORTANCE Despite the eradication of smallpox, some orthopoxviruses remain important human pathogens, as exemplified by the recent 2022 monkeypox virus (MPXV) outbreak. Although smallpox vaccines are effective against MPXV, access to those vaccines is limited. In addition, current antiviral treatment against MPXV infections is limited to the use of the FDA-approved drugs tecovirimat and brincidofovir. Thus, there is an urgent need to identify novel antivirals for the treatment of MPXV infection and other potentially zoonotic orthopoxvirus infections. Here, we show that 13 compounds, derived from two different libraries, previously found to inhibit several RNA viruses, also inhibit VACV. Notably, 11 compounds also displayed inhibitory activity against MPXV. |
| first_indexed | 2024-03-12T14:31:24Z |
| format | Article |
| id | doaj.art-6e00faebab264f118191ce0ac431106c |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-03-12T14:31:24Z |
| publishDate | 2023-08-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-6e00faebab264f118191ce0ac431106c2023-08-17T13:04:14ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972023-08-0111410.1128/spectrum.04745-22Identification of In Vitro Inhibitors of Monkeypox ReplicationKevin Chiem0Aitor Nogales1Maria Lorenzo2Desarey Morales Vasquez3Yan Xiang4Yogesh K. Gupta5Rafael Blasco6Juan Carlos de la Torre7Luis Martínez-Sobrido8Texas Biomedical Research Institute, San Antonio, Texas, USAAnimal Health Research Centre, Centro Nacional Instituto de Investigación y Tecnología Agraria y Alimentaria, Madrid, SpainDepartamento de Biotecnología, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, Madrid, SpainTexas Biomedical Research Institute, San Antonio, Texas, USADepartment of Microbiology, Immunology & Molecular Genetics, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USADepartment of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USADepartamento de Biotecnología, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, Madrid, SpainDepartment of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USATexas Biomedical Research Institute, San Antonio, Texas, USAABSTRACT Monkeypox virus (MPXV) infections in humans have historically been restricted to regions of endemicity in Africa. However, in 2022, an alarming number of MPXV cases were reported globally, with evidence of person-to-person transmission. Because of this, the World Health Organization (WHO) declared the MPXV outbreak a public health emergency of international concern. The supply of MPXV vaccines is limited, and only two antivirals, tecovirimat and brincidofovir, approved by the U.S. Food and Drug Administration (FDA) for the treatment of smallpox, are currently available for the treatment of MPXV infection. Here, we evaluated 19 compounds previously shown to inhibit different RNA viruses for their ability to inhibit orthopoxvirus infections. We first used recombinant vaccinia virus (rVACV) expressing fluorescence (mScarlet or green fluorescent protein [GFP]) and luciferase (Nluc) reporter genes to identify compounds with antiorthopoxvirus activity. Seven compounds from the ReFRAME library (antimycin A, mycophenolic acid, AVN-944, pyrazofurin, mycophenolate mofetil, azaribine, and brequinar) and six compounds from the NPC library (buparvaquone, valinomycin, narasin, monensin, rotenone, and mubritinib) showed inhibitory activity against rVACV. Notably, the anti-VACV activity of some of the compounds in the ReFRAME library (antimycin A, mycophenolic acid, AVN-944, mycophenolate mofetil, and brequinar) and all the compounds from the NPC library (buparvaquone, valinomycin, narasin, monensin, rotenone, and mubritinib) were confirmed with MPXV, demonstrating their inhibitory activity in vitro against two orthopoxviruses. IMPORTANCE Despite the eradication of smallpox, some orthopoxviruses remain important human pathogens, as exemplified by the recent 2022 monkeypox virus (MPXV) outbreak. Although smallpox vaccines are effective against MPXV, access to those vaccines is limited. In addition, current antiviral treatment against MPXV infections is limited to the use of the FDA-approved drugs tecovirimat and brincidofovir. Thus, there is an urgent need to identify novel antivirals for the treatment of MPXV infection and other potentially zoonotic orthopoxvirus infections. Here, we show that 13 compounds, derived from two different libraries, previously found to inhibit several RNA viruses, also inhibit VACV. Notably, 11 compounds also displayed inhibitory activity against MPXV.https://journals.asm.org/doi/10.1128/spectrum.04745-22antiviralsGFPluciferasemonkeypoxorthopoxviruspoxvirus |
| spellingShingle | Kevin Chiem Aitor Nogales Maria Lorenzo Desarey Morales Vasquez Yan Xiang Yogesh K. Gupta Rafael Blasco Juan Carlos de la Torre Luis Martínez-Sobrido Identification of In Vitro Inhibitors of Monkeypox Replication Microbiology Spectrum antivirals GFP luciferase monkeypox orthopoxvirus poxvirus |
| title | Identification of In Vitro Inhibitors of Monkeypox Replication |
| title_full | Identification of In Vitro Inhibitors of Monkeypox Replication |
| title_fullStr | Identification of In Vitro Inhibitors of Monkeypox Replication |
| title_full_unstemmed | Identification of In Vitro Inhibitors of Monkeypox Replication |
| title_short | Identification of In Vitro Inhibitors of Monkeypox Replication |
| title_sort | identification of in vitro inhibitors of monkeypox replication |
| topic | antivirals GFP luciferase monkeypox orthopoxvirus poxvirus |
| url | https://journals.asm.org/doi/10.1128/spectrum.04745-22 |
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