Adenosine N1-oxide inhibits vaccinia virus replication by blocking translation of viral early mRNAs

Kane, Eileen; Shuman, Stewart

doi:10.1128/jvi.69.10.6352-6358.1995

Cited by 17 publications

(4 citation statements)

References 36 publications

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“…Next, we aimed to determine the role of early gene expression, which coincides with viral uncoating ( 38 ), in the cGAS-dependent response to MVA infection. We infected MDDCs with ultraviolet (UV)–irradiated MVA (MVAUV), to cross-link nucleic acids and prevent viral gene expression, or added adenosine N 1 -oxide (ANO) during MVA infection, which preserves early mRNA expression but blocks early gene translation ( 39 ). MVAGFP expression was completely abrogated upon MVAUV infection, whereas residual MVAGFP expression was detected with ANO (fig.…”

Section: Resultsmentioning

confidence: 99%

Single-cell analysis reveals divergent responses of human dendritic cells to the MVA vaccine

et al. 2021

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Modified vaccinia Ankara (MVA) is a live, attenuated human smallpox vaccine and a vector for the development of new vaccines against infectious diseases and cancer. Efficient activation of the immune system by MVA partially relies on its encounter with dendritic cells (DCs). MVA infection of DCs leads to multiple outcomes, including cytokine production, activation of costimulatory molecules for T cell stimulation, and cell death. Here, we examined how these diverse responses are orchestrated in human DCs. Single-cell analyses revealed that the response to MVA infection in DCs was limited to early viral gene expression. In response to the early events in the viral cycle, we found that DCs grouped into three distinct clusters. A cluster of infected cells sensed the MVA genome by the intracellular innate immunity pathway mediated by cGAS, STING, TBK1, and IRF3 and subsequently produced inflammatory cytokines. In response to these cytokines, a cluster of noninfected bystander cells increased costimulatory molecule expression. A separate cluster of infected cells underwent caspase-dependent apoptosis. Induction of apoptosis persisted after inhibition of innate immunity pathway mediators independently of previously described IRF-dependent or replication-dependent pathways and was a response to early MVA gene expression. Together, our study identified multiple mechanisms that underlie the interactions of MVA with human DCs.

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Section: Resultsmentioning

confidence: 99%

Single-cell analysis reveals divergent responses of human dendritic cells to the MVA vaccine

et al. 2021

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“…Cell monolayers in 384-well plates were infected at an MOI of ϳ0.006 with a recombinant virus that expresses karyophilic GFP under the control of a viral early/late promoter (38), and the plates were scanned for green fluorescence at 3 days postinfection. The test compounds were included in the medium at the time of infection at a concentration of 10 M. ANO (10 g/ml) was used as a positive control for complete inhibition of viral gene expression (26). The screen was performed twice.…”

Section: Resultsmentioning

confidence: 99%

Identification of Novel Antipoxviral Agents: Mitoxantrone Inhibits Vaccinia Virus Replication by Blocking Virion Assembly

Deng¹,

Dai

Ciro

et al. 2007

J Virol

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The bioterror threat of a smallpox outbreak in an unvaccinated population has mobilized efforts to develop new antipoxviral agents. By screening a library of known drugs, we identified 13 compounds that inhibited vaccinia virus replication at noncytotoxic doses. The anticancer drug mitoxantrone is unique among the inhibitors identified in that it has no apparent impact on viral gene expression. Rather, it blocks processing of viral structural proteins and assembly of mature progeny virions. The isolation of mitoxantrone-resistant vaccinia strains underscores that a viral protein is the likely target of the drug. Whole-genome sequencing of mitoxantrone-resistant viruses pinpointed missense mutations in the N-terminal domain of vaccinia DNA ligase. Despite its favorable activity in cell culture, mitoxantrone administered intraperitoneally at the maximum tolerated dose failed to protect mice against a lethal intranasal infection with vaccinia virus.Poxviruses have been at the forefront of advances in medicine for 200 years, from Jenner's paper on the efficacy of vaccination against smallpox in 1798 to the successful use of vaccinia virus to eradicate human smallpox disease, as proclaimed by the World Health Organization in 1977. Throughout the 1990s, the scientific community debated the proposed destruction of the last known stocks of smallpox virus (24, 31). Hanging over this discussion was the fear that undeclared stocks of smallpox could be used as a bioterror weapon against an unvaccinated population. The urgency of this threat was amplified by the terrorist attacks of 2001, followed by the dissemination of anthrax via the postal service. The outbreak of human monkeypox infections in the United States in 2003 further highlighted the risks of reemergence of human poxvirus disease.Public health and research efforts have been mobilized accordingly to (i) exploit a modified live smallpox vaccine that maintains efficacy while minimizing complications, (ii) pursue alternatives to live vaccination for smallpox prophylaxis, and (iii) discover and bring forward for FDA approval new antipoxviral drugs. Two very different clinical scenarios present different challenges for drug therapy. Prophylaxis of a low-risk population in the event of a threat or actual outbreak mandates an orally available drug with minimal side effects. In contrast, the treatment of confirmed cases of smallpox (which can have a Ն30% fatality rate) need not be hindered by concerns about route of administration and non-life-threatening side effects. The goal is to have at least two approved antipoxviral drugs that act on different molecular targets.Although many inhibitors of poxvirus replication in culture or animal models have been described previously (50), the initial efforts post-2001 focused on the nucleoside analog cidofovir, an inhibitor of the viral DNA polymerase (28), which was already FDA approved for treatment of cytomegalovirus retinitis. Cidofovir was found to be effective in animal models of orthopoxvirus infection (37,50,53). However,...

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“…In a study on BSC40 cells infected with the vaccinia virus, DNA replication and viral translation were found to be completely inhibited. These findings suggested the antipoxvirus effects of ANO [47]. ANO inhibits the mRNA translation of poxvirus by incorporating adenosine analogs in viral mRNA [34].…”

Section: Drugs For the Treatment Of Mpox Virus Infectionmentioning

confidence: 99%

Update on monkeypox virus infection: Focusing current treatment and prevention approaches

Dhapola,

Kumari,

Sharma

et al. 2024

Fundamemntal Clinical Pharma

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BackgroundWhile the world is still facing the global pandemic COVID‐19, another zoonosis monkeypox (Mpox) has emerged posing a great threat to society. Insight into the pathogenesis, symptoms, and management strategies will aid in the development of potent therapeutics for the treatment of monkeypox virus infection.ObjectivesTo get insight into the current treatment and prevention strategies will aid in effectively coping with the disease.MethodsFor obtaining information regarding the ongoing treatment and prevention strategies and the drugs under pipeline, we referred to Google Scholar, Pub Med, Pub Chem, and WHO official site.ResultsThere are a few drugs that came out to be effective for the treatment of Mpox. Tecovirimat acts by inhibiting viral replication and viral wrapping. Another drug is cidofovir, which hinders the activity of viral DNA polymerase but has the drawback of nephrotoxicity. To overcome this, a conjugate of cidofovir is being used—known as brincidofovir—which has a similar mechanism as cidofovir but lesser toxicity. Ribavirin acts via inhibiting inosine monophosphate dehydrogenase (IMPDPH) thus disrupting viral translation. It also interferes with helicase activity. Tiazofurin, Adenosine N1 oxide, and HPMPA have shown efficacy in in‐vitro studies by inhibiting IMPDH, DNA polymerase, and viral mRNA translation respectively. In‐silico studies have proven the effect of nilotinib, simeprevir, and dihydroergotamine for Mpox treatment. They have shown binding affinity for proteins required for the growth and release of MPXV. Vaccines have also been employed for the prevention of Mpox, which includes JYNNEOS, ACAM2000, and VIGIV.ConclusionThis review highlights the pathogenesis of the virus, disease manifestations, drugs, and vaccines that are being used and those under pipeline for the treatment and prevention of Mpox.

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Adenosine N1-oxide inhibits vaccinia virus replication by blocking translation of viral early mRNAs

Cited by 17 publications

References 36 publications

Single-cell analysis reveals divergent responses of human dendritic cells to the MVA vaccine

Single-cell analysis reveals divergent responses of human dendritic cells to the MVA vaccine

Identification of Novel Antipoxviral Agents: Mitoxantrone Inhibits Vaccinia Virus Replication by Blocking Virion Assembly

Update on monkeypox virus infection: Focusing current treatment and prevention approaches

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