An Overview of Antivirals against Monkeypox Virus and Other Orthopoxviruses

Abstract

The current monkeypox outbreaks during the COVID-19 pandemic have reignited interest in orthopoxvirus antivirals. Monkeypox belongs to the Orthopoxvirus genus of the Poxviridae family, which also includes the variola virus, vaccinia virus, and cowpox virus. Two orally bioavailable drugs, tecovirimat and brincidofovir, have been approved for treating smallpox infections. Given their human safety profiles and in vivo antiviral efficacy in animal models, both drugs have also been recommended to treat monkeypox infection. To facilitate the development of additional orthopoxvirus antivirals, we summarize the antiviral activity, mechanism of action, and mechanism of resistance of orthopoxvirus antivirals. This perspective covers both direct-acting and host-targeting antivirals with an emphasis on drug candidates showing in vivo antiviral efficacy in animal models. We hope to speed the orthopoxvirus antiviral drug discovery by providing medicinal chemists with insights into prioritizing proper drug targets and hits for further development.

Exploring monkeypox virus proteins and rapid detection techniques

“…Furthermore, MD analysis confirmed the drug’s efficacy against mpox ( Li et al., 2022a ). Additionally, there are recent studies that provide an overview of potential antivirals against P37 ( Wang et al., 2023b ; Ashley et al., 2024 ) and other mpox proteins ( Bajrai et al., 2022 ; Kaur et al., 2023 ).…”

Immunopathogenesis of Orthopoxviridae: Insights into Immunology from Smallpox to Monkeypox (Mpox)

“…For specific antiviral therapy in adults and children weighing over 13kg, early indications that an antiviral tecovirimat approved in the European Union (EU) may be beneficial (see Supplementary Materials). Other antivirals of consideration for MPXV infections include intravenous vaccinia immunoglobulins (VIGIV), and brincidofovir [184,185]. These indications potentially could include the treatment of other OPXV infections like VACV, MPXV, and cow poxvirus (CPXV), although this would need to be confirmed.…”

“…Brincidofovir is an experimental anti−viral agent against several viruses and is a competitive substrate inhibitor of viral dsDNA polymerases [188]. Brincidofovir has been conjugated to a lipid for slower plasma release, that is then cleaved and metabolized to the active ingredient cidofovir diphosphate intracellularly for plasma release to prevent extracellular virion release [185,188]. However, it is also effective against EBOV (see Supplementary Materials) [189][190][191][192].…”

Antiviral activities of two nucleos(t)ide analogs against vaccinia, mpox, and cowpox viruses in primary human fibroblasts

“…Therefore, it is critically important to develop new chemical entities against orthopoxviruses to provide valuable leads for rapid and effective countermeasures against re-emerging smallpox, mpox outbreaks, and other emerging orthopoxviruses. While many antiviral candidates against poxviruses have been identified in the past years ( Wang et al, 2023 ; Siegrist and Sassine 2023 ), the majority of them have not been further characterized.

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