Orally available nucleoside analog UMM-766 provides protection in a murine model of orthopox disease
ABSTRACTAlthough smallpox has been eradicated, other orthopoxviruses continue to be a public health concern as exemplified by the ongoing Mpox (formerly monkeypox) global outbreak. While medical countermeasures (MCMs) previously approved by the Food and Drug Administration for the treatment of small...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2024-04-01
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| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.03586-23 |
| _version_ | 1797228838464258048 |
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| author | Rajini R. Mudhasani Joseph W. Golden Gregory C. Adam Timothy J. Hartingh Krishna P. Kota David Ordonez Corey R. Quackenbush Julie P. Tran Curtis Cline Janice A. Williams Xiankun Zeng David B. Olsen Linda A. Lieberman Christopher Boyce Anthony Ginnetti J. Matthew Meinig Rekha G. Panchal Eric M. Mucker |
| author_facet | Rajini R. Mudhasani Joseph W. Golden Gregory C. Adam Timothy J. Hartingh Krishna P. Kota David Ordonez Corey R. Quackenbush Julie P. Tran Curtis Cline Janice A. Williams Xiankun Zeng David B. Olsen Linda A. Lieberman Christopher Boyce Anthony Ginnetti J. Matthew Meinig Rekha G. Panchal Eric M. Mucker |
| author_sort | Rajini R. Mudhasani |
| collection | DOAJ |
| description | ABSTRACTAlthough smallpox has been eradicated, other orthopoxviruses continue to be a public health concern as exemplified by the ongoing Mpox (formerly monkeypox) global outbreak. While medical countermeasures (MCMs) previously approved by the Food and Drug Administration for the treatment of smallpox have been adopted for Mpox, previously described vulnerabilities coupled with the questionable benefit of at least one of the therapeutics during the 2022 Mpox outbreak reinforce the need for identifying and developing other MCMs against orthopoxviruses. Here, we screened a panel of Merck proprietary small molecules and identified a novel nucleoside inhibitor with potent broad-spectrum antiviral activity against multiple orthopoxviruses. Efficacy testing of a 7-day dosing regimen of the orally administered nucleoside in a murine model of severe orthopoxvirus infection yielded a dose-dependent increase in survival. Treated animals had greatly reduced lesions in the lung and nasal cavity, particularly in the 10 µg/mL dosing group. Viral levels were also markedly lower in the UMM-766-treated animals. This work demonstrates that this nucleoside analog has anti-orthopoxvirus efficacy and can protect against severe disease in a murine orthopox model.IMPORTANCEThe recent monkeypox virus pandemic demonstrates that members of the orthopoxvirus, which also includes variola virus, which causes smallpox, remain a public health issue. While currently FDA-approved treatment options exist, risks that resistant strains of orthopoxviruses may arise are a great concern. Thus, continued exploration of anti-poxvirus treatments is warranted. Here, we developed a template for a high-throughput screening assay to identify anti-poxvirus small-molecule drugs. By screening available drug libraries, we identified a compound that inhibited orthopoxvirus replication in cell culture. We then showed that this drug can protect animals against severe disease. Our findings here support the use of existing drug libraries to identify orthopoxvirus-targeting drugs that may serve as human-safe products to thwart future outbreaks. |
| first_indexed | 2024-04-24T15:03:03Z |
| format | Article |
| id | doaj.art-53df8f67d29d4344baea9e9e6311d3a1 |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-04-24T15:03:03Z |
| publishDate | 2024-04-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-53df8f67d29d4344baea9e9e6311d3a12024-04-02T14:16:18ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972024-04-0112410.1128/spectrum.03586-23Orally available nucleoside analog UMM-766 provides protection in a murine model of orthopox diseaseRajini R. Mudhasani0Joseph W. Golden1Gregory C. Adam2Timothy J. Hartingh3Krishna P. Kota4David Ordonez5Corey R. Quackenbush6Julie P. Tran7Curtis Cline8Janice A. Williams9Xiankun Zeng10David B. Olsen11Linda A. Lieberman12Christopher Boyce13Anthony Ginnetti14J. Matthew Meinig15Rekha G. Panchal16Eric M. Mucker17Molecular Biology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USAVirology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USAQuantitative Biosciences, Merck & Co. Inc., Rahway, New Jersey, USADiscovery Chemistry, Merck & Co. Inc., Rahway, New Jersey, USAMolecular Biology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USAMolecular Biology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USAMolecular Biology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USAMolecular Biology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USAPathology, Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USAPathology, Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USAPathology, Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USAInfectious Diseases and Vaccines, Merck & Co. Inc., Rahway, New Jersey, USADiscovery Immunology, Merck & Co. Inc., Rahway, New Jersey, USADiscovery Pharmaceutical Sciences, Merck & Co. Inc., Rahway, New Jersey, USADiscovery Chemistry, Merck & Co. Inc., Rahway, New Jersey, USABacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USAMolecular Biology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USAVirology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USAABSTRACTAlthough smallpox has been eradicated, other orthopoxviruses continue to be a public health concern as exemplified by the ongoing Mpox (formerly monkeypox) global outbreak. While medical countermeasures (MCMs) previously approved by the Food and Drug Administration for the treatment of smallpox have been adopted for Mpox, previously described vulnerabilities coupled with the questionable benefit of at least one of the therapeutics during the 2022 Mpox outbreak reinforce the need for identifying and developing other MCMs against orthopoxviruses. Here, we screened a panel of Merck proprietary small molecules and identified a novel nucleoside inhibitor with potent broad-spectrum antiviral activity against multiple orthopoxviruses. Efficacy testing of a 7-day dosing regimen of the orally administered nucleoside in a murine model of severe orthopoxvirus infection yielded a dose-dependent increase in survival. Treated animals had greatly reduced lesions in the lung and nasal cavity, particularly in the 10 µg/mL dosing group. Viral levels were also markedly lower in the UMM-766-treated animals. This work demonstrates that this nucleoside analog has anti-orthopoxvirus efficacy and can protect against severe disease in a murine orthopox model.IMPORTANCEThe recent monkeypox virus pandemic demonstrates that members of the orthopoxvirus, which also includes variola virus, which causes smallpox, remain a public health issue. While currently FDA-approved treatment options exist, risks that resistant strains of orthopoxviruses may arise are a great concern. Thus, continued exploration of anti-poxvirus treatments is warranted. Here, we developed a template for a high-throughput screening assay to identify anti-poxvirus small-molecule drugs. By screening available drug libraries, we identified a compound that inhibited orthopoxvirus replication in cell culture. We then showed that this drug can protect animals against severe disease. Our findings here support the use of existing drug libraries to identify orthopoxvirus-targeting drugs that may serve as human-safe products to thwart future outbreaks.https://journals.asm.org/doi/10.1128/spectrum.03586-23orthopoxvirusnucleosidevacciniamonkeypoxMpoxmurine |
| spellingShingle | Rajini R. Mudhasani Joseph W. Golden Gregory C. Adam Timothy J. Hartingh Krishna P. Kota David Ordonez Corey R. Quackenbush Julie P. Tran Curtis Cline Janice A. Williams Xiankun Zeng David B. Olsen Linda A. Lieberman Christopher Boyce Anthony Ginnetti J. Matthew Meinig Rekha G. Panchal Eric M. Mucker Orally available nucleoside analog UMM-766 provides protection in a murine model of orthopox disease Microbiology Spectrum orthopoxvirus nucleoside vaccinia monkeypox Mpox murine |
| title | Orally available nucleoside analog UMM-766 provides protection in a murine model of orthopox disease |
| title_full | Orally available nucleoside analog UMM-766 provides protection in a murine model of orthopox disease |
| title_fullStr | Orally available nucleoside analog UMM-766 provides protection in a murine model of orthopox disease |
| title_full_unstemmed | Orally available nucleoside analog UMM-766 provides protection in a murine model of orthopox disease |
| title_short | Orally available nucleoside analog UMM-766 provides protection in a murine model of orthopox disease |
| title_sort | orally available nucleoside analog umm 766 provides protection in a murine model of orthopox disease |
| topic | orthopoxvirus nucleoside vaccinia monkeypox Mpox murine |
| url | https://journals.asm.org/doi/10.1128/spectrum.03586-23 |
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