Potential therapeutic targets for Mpox: the evidence to date

ABSTRACTIntroduction The global Mpox (MPX) disease outbreak caused by the Mpox virus (MPXV) in 2022 alarmed the World Health Organization (WHO) and health regulation agencies of individual countries leading to the declaration of MPX as a Public Health Emergency. Owing to the genetic similarities between smallpox-causing poxvirus and MPXV, vaccine JYNNEOS, and anti-smallpox drugs Brincidofovir and Tecovirimat were granted emergency use authorization by the United States Food and Drug Administration. The WHO also included cidofovir, NIOCH-14, and other vaccines as treatment options.Areas covered This article covers the historical development of EUA-granted antivirals, resistance to these antivirals, and the projected impact of signature mutations on the potency of antivirals against currently circulating MPXV. Since a high prevalence of MPXV infections in individuals coinfected with HIV and MPXV, the treatment results among these individuals have been included.Expert opinion All EUA-granted drugs have been approved for smallpox treatment. These antivirals show good potency against Mpox. However, conserved resistance mutation positions in MPXV and related poxviruses, and the signature mutations in the 2022 MPXV can potentially compromise the efficacy of the EUA-granted treatments. Therefore, MPXV-specific medications are required not only for the current but also for possible future outbreaks.KEYWORDS: MpoxCidofovirBrincidofovirBrincidofovirTecovirimatOPG71OPG57F8LC19L Article highlights The 2022 Mpox outbreak and the volume of infections showed that poxviruses remain a constant threat to global health. Signature mutations in currently circulating Mpox viruses (MPXV) may be contributing in unknown ways to the outbreak. Therefore, the role of these mutations in viral replication needs to be established.There are no Mpox-specific treatments available. Limited studies indicate that the treatments that have been granted emergency use authorization (EUA) have good efficacy against MPXV. However, additional, and more robust studies are needed to establish the potency of these drugs against MPXV.Nucleic acid polymerases are the most sought-after antiviral targets. Considering their essential role in virus replication, research to discover poxvirus DNA polymerase inhibitors is needed. Additionally, other components of the viral DNA replication holoenzyme, such as DNA helicase, should be extensively characterized so that new antivirals can be developed against such targets.The current MPXV was most prevalent among a specific group of individuals (men who have sex with men, and bisexuals). Many of these individuals are coinfected with HIV and MPXV. Therefore, drugs targeting MPXV and HIV coinfection need to be developed.Abbreviations BCV=BrincidofovirBPXV=Buffalopox virusCDV=CidofovirCPXV=Cowpox virusC19L -=Mpox phospholipase D-like proteinEUA=Emergency Use AuthorizationEV=enveloped virionF8L=Mpox DNA polymeraseHBV=hepatitis B virusHCV=hepatitis C virusHIV=human papillomavirusHSV1=herpes simplex virusKF=Klenow FragmentMPX=Mpox virusMV=mature virionOPG=Orthopoxvirus genePCNA=Proliferation Cell Nuclear AntigenPHE=Public Health EmergencyTAF=tenofovir alafenamideTDF=tenofovir disoproxilUS-HHS=United States Human Health Services AdministrationVACV=Vaccinia virusVARV=variola virusvRNAP=DNA-dependent RNA polymeraseWHO=World Health OrganizationWV=wrapped virionAcknowledgmentsK. Singh acknowledges the computation facilities of the Molecular Interactions Core at the University of Missouri, Columbia, MO 65212. We also thank numerous laboratories that have enormously contributed to poxvirus research, but we could not cite their work.Declaration of interestCL. Lorson is cofounder and chief scientific officer of Shift Pharmaceuticals. CL. Lorson has received in excess of $10,000 in income per annum from Shift Pharmaceuticals. CL. Lorson and MU share patents on compounds licensed by Shift Pharmaceuticals and planned patents for additional compounds (United States patent nos. 9,885,040; 10,472,630; and 11,136,580). K Singh is chief scientific officer for Sanctum Therapeutics Corporation. K Singh has received in excess of $10,000 in income per annum from Sanctum Therapeutics Corporation. K Singh and MU share patents on compounds licensed by Sanctum Therapeutics Corporation and planned patents for additional compounds (United States patent nos. US16/311,136; PCT/US2020/36658; US 63/262,611; US 63/200,366). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Additional informationFundingK Singh was partially funded by the Bond Life Sciences Center (Early Concept grant), a subcontract from Emory University (5R37AI076119), and the University of Missouri startup support.