Orally available nucleoside analog UMM-766 provides protection in a murine model of orthopox disease.

Autor:	Mudhasani RR; Molecular Biology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USA., Golden JW; Virology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USA., Adam GC; Quantitative Biosciences, Merck & Co. Inc., Rahway, New Jersey, USA., Hartingh TJ; Discovery Chemistry, Merck & Co. Inc., Rahway, New Jersey, USA., Kota KP; Molecular Biology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USA., Ordonez D; Molecular Biology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USA., Quackenbush CR; Molecular Biology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USA., Tran JP; Molecular Biology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USA., Cline C; Pathology, Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USA., Williams JA; Pathology, Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USA., Zeng X; Pathology, Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USA., Olsen DB; Infectious Diseases and Vaccines, Merck & Co. Inc., Rahway, New Jersey, USA., Lieberman LA; Discovery Immunology, Merck & Co. Inc., Rahway, New Jersey, USA., Boyce C; Discovery Pharmaceutical Sciences, Merck & Co. Inc., Rahway, New Jersey, USA., Ginnetti A; Discovery Chemistry, Merck & Co. Inc., Rahway, New Jersey, USA., Meinig JM; Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USA., Panchal RG; Molecular Biology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USA., Mucker EM; Virology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USA.
Jazyk:	angličtina
Zdroj:	Microbiology spectrum [Microbiol Spectr] 2024 Apr 02; Vol. 12 (4), pp. e0358623. Date of Electronic Publication: 2024 Feb 23.
DOI:	10.1128/spectrum.03586-23
Abstrakt:	Although 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. Competing Interests: K.P.K., D.O., C.R.Q., J.P.T., and C.C. are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Rahway, NJ, USA, and may own stock or hold stock options in Merck & Co. Inc., Rahway, NJ, USA.
Databáze:	MEDLINE
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