In Vitro Antiviral Activity of Mycophenolic Acid and Its Reversal by Guanine-Type Compounds

Cline, J. C.; Nelson, Janet D.; Gerzon, K.; Williams, R. H.; Delong, D. C.

doi:10.1128/aem.18.1.14-20.1969

Cited by 41 publications

(12 citation statements)

References 5 publications

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“…Mycophenolic acid is an orally available immunosuppressant used for prevention of posttransplant organ rejection. Mycophenolic acid has activity against many RNA and DNA viruses (4,9,16,22,23,29,35,43), including poxviruses (9,19,49). Its antiviral activity is linked to inhibition of purine metabolism, insofar as virus replication is rescued by exogenous guanosine.…”

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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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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“…This drug was approved in 1995 (USFDA) for preventing organ transplant rejection. MPA was earlier shown to be effective against a range of unrelated viruses, with antiviral activity being reversed by administration of guanine type of compounds [ 137 ]. This indicated their ability to interfere in viral nucleic acid synthesis, and now they are recognized as non-competitive inhibitors of inosine-5′-monophosphate dehydrogenase (IMPDH) [ 138 ].…”

Section: Inhibitors Of Viral Genome Replicationmentioning

confidence: 99%

Current Strategies for Inhibition of Chikungunya Infection

Subudhi

Chattopadhyay

Mishra

et al. 2018

Viruses

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Increasing incidences of Chikungunya virus (CHIKV) infection and co-infections with Dengue/Zika virus have highlighted the urgency for CHIKV management. Failure in developing effective vaccines or specific antivirals has fuelled further research. This review discusses updated strategies of CHIKV inhibition and provides possible future directions. In addition, it analyzes advances in CHIKV lifecycle, drug-target development, and potential hits obtained by in silico and experimental methods. Molecules identified with anti-CHIKV properties using traditional/rational drug design and their potential to succeed in subsequent stages of drug development have also been discussed. Possibilities of repurposing existing drugs based on their in vitro findings have also been elucidated. Probable modes of interference of these compounds at various stages of infection, including entry and replication, have been highlighted. The use of host factors as targets to identify antivirals against CHIKV has been addressed. While most of the earlier antivirals were effective in the early phases of the CHIKV life cycle, this review is also focused on drug candidates that are effective at multiple stages of its life cycle. Since most of these antivirals require validation in preclinical and clinical models, the challenges regarding this have been discussed and will provide critical information for further research.

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“…37). This antibiotic blocks the replication of several animal viruses, including some retroviruses (Williams et al, 1968), EMC virus and coxsackie virus Cline et al, 1969;Planterose, 1969). It is still uncertain if this blockade is due simply to cellular toxicity.…”

Section: Mycophenolic Acidmentioning

confidence: 99%

Picornavirus inhibitors

Carrasco

1994

Pharmacology & Therapeutics

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Picornaviruses are among the best understood animal viruses in molecular terms. A number of important human and animal pathogens are members of the Picornaviridae family. The genome organization, the different steps of picornavirus growth and numerous compounds that have been reported as inhibitors of picornavirus functions are reviewed. The picornavirus particles and several agents that interact with them have been solved at atomic resolution, leading to computer-assisted drug design. Picornavirus inhibitors are useful in aiding a better understanding of picornavirus biology. In addition, some of them are promising therapeutic agents. Clinical efficacy of agents that bind to picornavirus particles has already been demonstrated.

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In Vitro Antiviral Activity of Mycophenolic Acid and Its Reversal by Guanine-Type Compounds

Cited by 41 publications

References 5 publications

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

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

Current Strategies for Inhibition of Chikungunya Infection

Picornavirus inhibitors

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