Potential antiviral therapeutics for smallpox, monkeypox and other orthopoxvirus infections

Baker, Richard L.; Bray, Mike; Huggins, John W.

doi:10.1016/s0166-3542(02)00196-1

Cited by 248 publications

(168 citation statements)

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“…They inhibited the growth of tumor cells in culture, 33) and vaccinia virus replication 34) by the blockade of translation of virus mRNAs. [35][36][37] But there have been no reports showing the distribution of adenosine derivatives with N 1 -oxide in natural products, or the activity on the nervous system. Therefore, it was (Fig.…”

Section: Discussionmentioning

confidence: 99%

Identification of AMPN₁-Oxide in Royal Jelly as a Component Neurotrophic toward Cultured Rat Pheochromocytoma PC12 Cells

Hattori

Nishimura

Mishima

et al. 2006

Bioscience, Biotechnology, and Biochemistry

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Section: Discussionmentioning

confidence: 99%

Identification of AMPN₁-Oxide in Royal Jelly as a Component Neurotrophic toward Cultured Rat Pheochromocytoma PC12 Cells

Hattori

Nishimura

Mishima

et al. 2006

Bioscience, Biotechnology, and Biochemistry

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“…Cidofovir is a potent antiviral drug that is currently being investigated for treating deadly smallpox (variola) and monkeypox, although it is licensed for human immunodeficiency virus-associated cytomegalovirus retinitis (1,5,26,31). Given the possibility that cidofovir or other antiviral drugs can limit initial active vaccinia virus replication, cidofovir and Dryvax (cidofovirϩDryvax) coadministration may reduce Dryvax-mediated vaccination complications.…”

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confidence: 99%

Coadministration of Cidofovir and Smallpox Vaccine Reduced Vaccination Side Effects but Interfered with Vaccine-Elicited Immune Responses and Immunity to Monkeypox

Wei

Huang

Fortman

et al. 2009

J Virol

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While the smallpox vaccine, Dryvax or Dryvax-derived ACAM2000, holds potential for public immunization against the spread of smallpox by bioterror, there is serious concern about Dryvax-mediated side effects. Here, we report that a single-dose vaccination regimen comprised of Dryvax and an antiviral agent, cidofovir, could reduce vaccinia viral loads after vaccination and significantly control Dryvax vaccination side effects. However, coadministration of cidofovir and Dryvax also reduced vaccine-elicited immune responses of antibody and T effector cells despite the fact that the reduced priming could be boosted as a recall response after monkeypox virus challenge. Evaluations of four different aspects of vaccine efficacy showed that coadministration of cidofovir and Dryvax compromised the Dryvax-induced immunity against monkeypox, although the covaccinated monkeys exhibited measurable protection against monkeypox compared to that of naïve controls. Thus, the single-dose coadministration of cidofovir and Dryvax effectively controlled vaccination side effects but significantly compromised vaccine-elicited immune responses and vaccine-induced immunity to monkeypox.

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“…Vaccination is not recommended for those with eczema and other exfoliative skin disorders or those with immunodeficiencies or for pregnant women. Therefore, the use of antiviral therapy in the event of a poxvirus outbreak or in the treatment of vaccination complications against smallpox virus (4) points to the continued need to examine available antiviral therapies as well as to develop new and more efficient treatment.Cidofovir (CDV) and cyclic CDV (cCDV) have been shown to be potent inhibitors of poxvirus replication in vitro (1,7,8,13) and in animal model studies (5, 10, 12); however, these compounds are inactive when given orally.Previous in vitro studies have shown that multiple-log increases in antiviral activity against orthopoxvirus replication (8), as well as enhanced inhibition of cytomegalovirus and herpesvirus replication by these esters (2), were observed with hexadecyloxypropyl (HDP) and octadecyloxyethyl (ODE) derivatives of CDV and cCDV (HDP-CDV, HDP-cCDV, ODE-CDV, and ODE-cCDV) compared to the results seen with the parent compounds. HDP-CDV, ODE-CDV, and oleyloxypropyl-CDV (OLP-CDV) have oral bioavailabilities of 88 to 93% in mice (6) and have oral activity against vaccinia virus (VV) and cowpox virus (CV) infections in mice (11).…”

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confidence: 99%

“…Cidofovir (CDV) and cyclic CDV (cCDV) have been shown to be potent inhibitors of poxvirus replication in vitro (1,7,8,13) and in animal model studies (5, 10, 12); however, these compounds are inactive when given orally.…”

mentioning

confidence: 99%

Inhibitory Activity of Alkoxyalkyl and Alkyl Esters of Cidofovir and Cyclic Cidofovir against Orthopoxvirus Replication In Vitro

Keith

Wan

Ciesla

et al. 2004

Antimicrob Agents Chemother

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A new series of ether lipid esters of cidofovir (CDV) were evaluated against vaccinia and cowpox viruses. Activity was dependent on number of atoms in the alkyl or alkoxyalkyl chain, the linker moiety, and the presence of a double bond in the alkoxyalkyl chains linked to the phosphonate moiety of CDV.The threat of an intentional or unintentional spread of poxvirus infections to a vulnerable population has led to increased efforts to find safe, rapidly deployable treatments against such infections. Although vaccination is now being offered to some healthcare workers and other "first responders," there are valid concerns about potential vaccine risks (3, 9). Vaccination is not recommended for those with eczema and other exfoliative skin disorders or those with immunodeficiencies or for pregnant women. Therefore, the use of antiviral therapy in the event of a poxvirus outbreak or in the treatment of vaccination complications against smallpox virus (4) points to the continued need to examine available antiviral therapies as well as to develop new and more efficient treatment.Cidofovir (CDV) and cyclic CDV (cCDV) have been shown to be potent inhibitors of poxvirus replication in vitro (1,7,8,13) and in animal model studies (5, 10, 12); however, these compounds are inactive when given orally.Previous in vitro studies have shown that multiple-log increases in antiviral activity against orthopoxvirus replication (8), as well as enhanced inhibition of cytomegalovirus and herpesvirus replication by these esters (2), were observed with hexadecyloxypropyl (HDP) and octadecyloxyethyl (ODE) derivatives of CDV and cCDV (HDP-CDV, HDP-cCDV, ODE-CDV, and ODE-cCDV) compared to the results seen with the parent compounds. HDP-CDV, ODE-CDV, and oleyloxypropyl-CDV (OLP-CDV) have oral bioavailabilities of 88 to 93% in mice (6) and have oral activity against vaccinia virus (VV) and cowpox virus (CV) infections in mice (11).In this study, the unmodified acyclic nucleoside phosphonates CDV and cCDV (along with a new series of analogs synthesized by esterification of these compounds with an alkyl chain with or without the propoxy-or ethoxy-linker moieties) were evaluated (using methodologies described previously) (7) for activity (plaque reduction assay) against VV and CV and for cytotoxicity (neutral red uptake assay) in human foreskin fibroblast (HFF) cells. To determine efficacy, briefly, HFF cells seeded in 6-well plates 2 days prior to use were infected with either VV or CV by the addition of 20 to 30 PFU per well. After a 1-h incubation period, various concentrations of drug were added to triplicate wells and plates were incubated at 37°C for 3 days. Toxicity was evaluated using HFF cells seeded in 96-well plates incubated with various concentrations of drug for 7 days at 37°C. After incubation, cell monolayers were stained with a 0.01% solution of neutral red. The compounds were synthesized as reported previously (8).As presented in Table 1, the most active ether lipid esters of CDV were OLE-CDV, ODBG-CDV, TDP-CDV, OLP-CDV, and ODP-...

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Potential antiviral therapeutics for smallpox, monkeypox and other orthopoxvirus infections

Cited by 248 publications

References 41 publications

Identification of AMPN₁-Oxide in Royal Jelly as a Component Neurotrophic toward Cultured Rat Pheochromocytoma PC12 Cells

Identification of AMPN₁-Oxide in Royal Jelly as a Component Neurotrophic toward Cultured Rat Pheochromocytoma PC12 Cells

Coadministration of Cidofovir and Smallpox Vaccine Reduced Vaccination Side Effects but Interfered with Vaccine-Elicited Immune Responses and Immunity to Monkeypox

Inhibitory Activity of Alkoxyalkyl and Alkyl Esters of Cidofovir and Cyclic Cidofovir against Orthopoxvirus Replication In Vitro

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Potential antiviral therapeutics for smallpox, monkeypox and other orthopoxvirus infections

Cited by 248 publications

References 41 publications

Identification of AMPN1-Oxide in Royal Jelly as a Component Neurotrophic toward Cultured Rat Pheochromocytoma PC12 Cells

Identification of AMPN1-Oxide in Royal Jelly as a Component Neurotrophic toward Cultured Rat Pheochromocytoma PC12 Cells

Coadministration of Cidofovir and Smallpox Vaccine Reduced Vaccination Side Effects but Interfered with Vaccine-Elicited Immune Responses and Immunity to Monkeypox

Inhibitory Activity of Alkoxyalkyl and Alkyl Esters of Cidofovir and Cyclic Cidofovir against Orthopoxvirus Replication In Vitro

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Identification of AMPN₁-Oxide in Royal Jelly as a Component Neurotrophic toward Cultured Rat Pheochromocytoma PC12 Cells

Identification of AMPN₁-Oxide in Royal Jelly as a Component Neurotrophic toward Cultured Rat Pheochromocytoma PC12 Cells