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Article: Orthopoxvirus inhibitors that are active in animal models: an update from 2008 to 2012.

Smee, Donald F

2015 Volume 8, Issue 9, Page(s) 891–901

Abstract: Antiviral agents are being sought as countermeasures for the potential deliberate release of smallpox (variola) and monkeypox viruses, for the treatment of naturally acquired monkeypox virus infections, and as therapy for complications due to smallpox ( ... ...

Abstract	Antiviral agents are being sought as countermeasures for the potential deliberate release of smallpox (variola) and monkeypox viruses, for the treatment of naturally acquired monkeypox virus infections, and as therapy for complications due to smallpox (live-attenuated vaccinia virus) vaccination or accidental infection after exposure to vaccinated persons. Reviews of the scientific literature spanning 1950-2008 have documented the progress made in developing small-animal models of poxvirus infection and identifying novel antiviral agents. Compounds of considerable interest include cidofovir, CMX001 and ST-246® (tecovirimat; SIGA Technologies, NY, USA). New inhibitors have been identified since 2008, most of which do not exhibit the kind of potency and selectivity required for drug development. Two promising agents include 4'-thioidoxuridine (a nucleoside analog) and mDEF201 (an adenovirus-vectored interferon). Compounds that have been effectively used in combination studies include vaccinia immune globulin, cidofovir, ST-246 and CMX001. In the future there may be an increase in experimental work using active compounds in combination.
Language	English
Publishing date	2015-03-24
Publishing country	England
Document type	Journal Article
ZDB-ID	2254606-6
ISSN	1746-0808 ; 1746-0794
ISSN (online)	1746-0808
ISSN	1746-0794
DOI	10.2217/fvl.13.76
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Article ; Online: Human IVIG treatment in a neurological disease model for Enterovirus A71 infection in 28-day-old AG129 mice.

Peterson, Christopher J / Hurst, Brett L / Evans, W Joseph / Van Wettere, Arnaud J / Gibson, Scott A / Smee, Donald F / Tarbet, E Bart

Virology

2023 Volume 580, Page(s) 62–72

Abstract: Enterovirus A71 can cause serious neurological disease in young children. Animal models for EV-A71 are needed to evaluate potential antiviral therapies. Existing models have limitations, including lack of lethality or crucial disease signs. Here we ... ...

Abstract	Enterovirus A71 can cause serious neurological disease in young children. Animal models for EV-A71 are needed to evaluate potential antiviral therapies. Existing models have limitations, including lack of lethality or crucial disease signs. Here we report the development of an EV-A71 model in 28-day-old mice. Virus was serially passaged until it produced consistent lethality and rear-limb paralysis. Onset of disease occurred between days 6-9 post-infection, with mortality following weight loss and neurological signs on days 9-14. In addition, a single administration of human intravenous immunoglobulin at doses of 200, 400 and 800 mg/kg at 4h post-infection was evaluated in the model. Protection from weight loss, neurological signs, and mortality (between 50 and 89%) were observed at doses of 400 mg/kg or greater. Based on these results, IVIG was selected for use as a positive control in this acute model, and suggest that IVIG is a potential therapeutic for EV-A71 infections.
MeSH term(s)	Child ; Humans ; Mice ; Animals ; Child, Preschool ; Immunoglobulins, Intravenous/therapeutic use ; Enterovirus Infections ; Enterovirus ; Enterovirus A, Human ; Nervous System Diseases ; Disease Models, Animal
Chemical Substances	Immunoglobulins, Intravenous
Language	English
Publishing date	2023-02-04
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	200425-2
ISSN	1096-0341 ; 0042-6822
ISSN (online)	1096-0341
ISSN	0042-6822
DOI	10.1016/j.virol.2023.02.002
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Article ; Online: Comparison of three dimensional synergistic analyses of percentage versus logarithmic data in antiviral studies.

Smee, Donald F / Prichard, Mark N

Antiviral research

2017 Volume 145, Page(s) 1–5

Abstract: Cell culture antiviral experiments were conducted in order to understand the relationship between percentage data generated by plaque reduction (PR) and logarithmic data derived by virus yield reduction (VYR) assays, using three-dimensional MacSynergy II ...

Abstract	Cell culture antiviral experiments were conducted in order to understand the relationship between percentage data generated by plaque reduction (PR) and logarithmic data derived by virus yield reduction (VYR) assays, using three-dimensional MacSynergy II software. The relationship between percentage and logarithmic data has not been investigated previously. Interpretation of drug-drug interactions is based on a Volume of Synergy (VS) calculation, which can be positive (synergy), negative (antagonistic), or neutral (no or minimal interaction). Interactions of two known inhibitors of vaccinia virus replication, cidofovir and 6-azauridine, used in combination by PR assay yielded a VS value of 265, indicative of strong synergy. By VYR, the VS value was only 37, or weak synergy using the same criterion, even though profound log
MeSH term(s)	Animals ; Antiviral Agents/pharmacology ; Azauridine/pharmacology ; Cercopithecus aethiops ; Cytosine/analogs & derivatives ; Cytosine/pharmacology ; Data Accuracy ; Data Interpretation, Statistical ; Drug Interactions ; Drug Synergism ; Humans ; Microbial Sensitivity Tests ; Organophosphonates/pharmacology ; Software ; Vaccinia virus/drug effects ; Vaccinia virus/growth & development ; Vero Cells ; Viral Plaque Assay ; Virus Replication/drug effects
Chemical Substances	Antiviral Agents ; Organophosphonates ; Azauridine (7BVB29RCPR) ; Cytosine (8J337D1HZY) ; cidofovir (JIL713Q00N)
Language	English
Publishing date	2017-07-01
Publishing country	Netherlands
Document type	Comparative Study ; Journal Article
ZDB-ID	306628-9
ISSN	1872-9096 ; 0166-3542
ISSN (online)	1872-9096
ISSN	0166-3542
DOI	10.1016/j.antiviral.2017.06.022
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Article ; Online: Combinations of L-N

Smee, Donald F / Dagley, Ashley / Tarbet, E B

Antiviral chemistry & chemotherapy

2017 Volume 25, Issue 1, Page(s) 11–17

Abstract: ... L- ... ...

Abstract	L-N
MeSH term(s)	Animals ; Antiviral Agents/pharmacology ; Disease Models, Animal ; Drug Synergism ; Enzyme Inhibitors/pharmacology ; Female ; Influenza A Virus, H1N1 Subtype/drug effects ; Influenza A Virus, H1N1 Subtype/isolation & purification ; Mice ; Mice, Inbred BALB C ; Orthomyxoviridae Infections/drug therapy ; Orthomyxoviridae Infections/virology ; Oseltamivir/pharmacology ; omega-N-Methylarginine/pharmacology
Chemical Substances	Antiviral Agents ; Enzyme Inhibitors ; Oseltamivir (20O93L6F9H) ; omega-N-Methylarginine (27JT06E6GR)
Language	English
Publishing date	2017-04
Publishing country	England
Document type	Journal Article
ZDB-ID	1033586-9
ISSN	2040-2066 ; 0956-3202
ISSN (online)	2040-2066
ISSN	0956-3202
DOI	10.1177/2040206617691885
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Article ; Online: Human IVIG treatment in a neurological disease model for Enterovirus A71 infection in 28-day-old AG129 mice

Peterson, Christopher J. / Hurst, Brett L. / Evans, W. Joseph / Van Wettere, Arnaud J. / Gibson, Scott A. / Smee, Donald F. / Tarbet, E. Bart

Virology. 2023 Feb. 04,

2023

Abstract	Enterovirus A71 can cause serious neurological disease in young children. Animal models for EV-A71 are needed to evaluate potential antiviral therapies. Existing models have limitations, including lack of lethality or crucial disease signs. Here we report the development of an EV-A71 model in 28-day-old mice. Virus was serially passaged until it produced consistent lethality and rear-limb paralysis. Onset of disease occurred between days 6–9 post-infection, with mortality following weight loss and neurological signs on days 9–14. In addition, a single administration of human intravenous immunoglobulin at doses of 200, 400 and 800 mg/kg at 4h post-infection was evaluated in the model. Protection from weight loss, neurological signs, and mortality (between 50-89%) were observed at doses of 400 mg/kg or greater. Based on these results, IVIG was selected for use as a positive control in this acute model, and suggest that IVIG is a potential therapeutic for EV-A71 infections.
Keywords	Enterovirus A ; death ; disease models ; humans ; immunoglobulins ; intravenous injection ; mortality ; nervous system diseases ; paralysis ; virology ; viruses ; weight loss ; Enterovirus A71 ; Animal model ; Neurological disease ; AG129 ; Intravenous immunoglobulin ; Therapeutics
Language	English
Dates of publication	2023-0204
Size	p. 62-72.
Publishing place	Elsevier Inc.
Document type	Article ; Online
Note	Pre-press version
ZDB-ID	200425-2
ISSN	1096-0341 ; 0042-6822
ISSN (online)	1096-0341
ISSN	0042-6822
DOI	10.1016/j.virol.2023.02.002
Database	NAL-Catalogue (AGRICOLA)

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Article: Progress in the discovery of compounds inhibiting orthopoxviruses in animal models.

Smee, Donald F

Antiviral chemistry & chemotherapy

2008 Volume 19, Issue 3, Page(s) 115–124

Abstract: Surrogate animal models must be used for testing antiviral agents against variola (smallpox) virus infections. Once developed, these, compounds can be stockpiled for use in the event of a bioterrorist incident involving either variola or monkeypox virus, ...

Abstract	Surrogate animal models must be used for testing antiviral agents against variola (smallpox) virus infections. Once developed, these, compounds can be stockpiled for use in the event of a bioterrorist incident involving either variola or monkeypox virus, or used to treat an occasional serious orthopoxvirus infection, such as disseminated vaccinia complication following exposure to the live virus vaccine. Recently, considerable progress has been made in the discovery of novel antiviral agents found active against orthopoxviruses in vivo. This includes the development of new animal models or refinement of existing ones for compound efficacy testing. Current mouse models employ ectromelia, cowpox and vaccinia (WR and IHD strains) viruses with respiratory (lung) or tail lesion infections commonly studied. Rabbitpox and vaccinia (WR strain) viruses are available for rabbit infections. Monkeypox and variola viruses are used for infecting monkeys. This review describes these and other animal models, and covers compounds found active in vivo from 2003 to date. Cidofovir, known to be active against orthopox virus infections prior to 2003, has been studied extensively over recent years. New compounds showing promise are orally active inhibitors of orthopoxvirus infections that include ether lipid prodrugs of cidofovir and (S)-HPMPA, ST-246, N-methanocarbathymidine (N-MCT) and SRI 21950 (a 4'-thio derivative of iododeoxyuridine). Another compound with high activity but requiring parenteral administration is HPMPO-DAPy. Further development of these compounds is warranted.
MeSH term(s)	Adenine/analogs & derivatives ; Adenine/pharmacology ; Animals ; Antiviral Agents/pharmacology ; Benzamides/pharmacology ; Cidofovir ; Cytosine/analogs & derivatives ; Cytosine/pharmacology ; Disease Models, Animal ; Drug Discovery ; Humans ; Isoindoles/pharmacology ; Organophosphonates/pharmacology ; Orthopoxvirus/drug effects ; Prodrugs/pharmacology
Chemical Substances	Antiviral Agents ; Benzamides ; Isoindoles ; Organophosphonates ; Prodrugs ; Cytosine (8J337D1HZY) ; 9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine (CJC8PO1KQ3) ; tecovirimat (F925RR824R) ; Adenine (JAC85A2161) ; Cidofovir (JIL713Q00N)
Language	English
Publishing date	2008-04-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1033586-9
ISSN	2040-2066 ; 0956-3202
ISSN (online)	2040-2066
ISSN	0956-3202
DOI	10.1177/095632020801900302
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Article ; Online: 2'-Fluoro-2'-deoxycytidine is a broad-spectrum inhibitor of bunyaviruses in vitro and in phleboviral disease mouse models.

Smee, Donald F / Jung, Kie-Hoon / Westover, Jonna / Gowen, Brian B

Antiviral research

2018 Volume 160, Page(s) 48–54

Abstract: 2'-Fluoro-2'-deoxycytidine (2'-FdC) was reported to inhibit various viruses in vitro, including Borna disease, hepatitis C, Lassa fever, influenza and certain herpes viruses, and is inhibitory to influenza viruses in mice. We investigated the antiviral ... ...

Abstract	2'-Fluoro-2'-deoxycytidine (2'-FdC) was reported to inhibit various viruses in vitro, including Borna disease, hepatitis C, Lassa fever, influenza and certain herpes viruses, and is inhibitory to influenza viruses in mice. We investigated the antiviral activity of 2'-FdC against several unrelated bunyaviruses in 50% cytopathic effect (CPE) inhibition assays and, with viruses that cause limited CPE, 90% virus yield reduction (VYR) assays. La Crosse (LACV), Maporal, Punta Toro, Rift Valley fever (RVFV), and San Angelo viruses were inhibited in CPE assays at 2.2-9.7 μM concentrations. In VYR assays, Heartland and severe fever with thrombocytopenia syndrome (SFTSV) viruses were inhibited at 0.9 and 3.7 μM, respectively. In contrast, ribavirin inhibited these viruses at an average of 47 μM. Antiviral efficacy studies were also conducted in mice infected with RVFV, SFTSV, and LACV. Against RVFV, 2'-FdC (100 and 200 mg/kg/day) and ribavirin (100 mg/kg/day) treatments each delayed mortality by approximately 6 days compared to placebo. Liver, spleen, and serum viral titers were significantly reduced by antiviral treatments. 2'-FdC (100 and 200 mg/kg/day) prevented death in SFTSV-infected mice, but was not as effective as favipiravir (100 mg/kg/day) based on body weight loss during infection. The 100 mg/kg/day doses of 2'-FdC and favipiravir significantly reduced liver, spleen, and serum viral titers. 2'-FdC and ribavirin afforded no protection against LACV infection in mice, which is encephalitic and thus inherently more difficult to treat. Taken together, our data suggest that 2'-FdC may be a viable candidate for treating certain non-encephalitic bunyavirus infections such as those caused by phleboviruses.
MeSH term(s)	Animal Structures/virology ; Animals ; Antiviral Agents/administration & dosage ; Antiviral Agents/pharmacology ; Body Weight ; Bunyaviridae Infections/drug therapy ; Cytopathogenic Effect, Viral ; DNA Viruses/drug effects ; DNA Viruses/growth & development ; Deoxycytidine/administration & dosage ; Deoxycytidine/analogs & derivatives ; Deoxycytidine/pharmacology ; Disease Models, Animal ; Mice ; Microbial Sensitivity Tests ; Placebos/administration & dosage ; RNA Viruses/drug effects ; RNA Viruses/growth & development ; Survival Analysis ; Treatment Outcome ; Viral Load
Chemical Substances	Antiviral Agents ; Placebos ; Deoxycytidine (0W860991D6) ; 2'-fluoro-2'-deoxycytidine (LCY080JPY9)
Language	English
Publishing date	2018-10-16
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	306628-9
ISSN	1872-9096 ; 0166-3542
ISSN (online)	1872-9096
ISSN	0166-3542
DOI	10.1016/j.antiviral.2018.10.013
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Article ; Online: Methods for evaluation of antiviral efficacy against influenza virus infections in animal models.

Smee, Donald F / Barnard, Dale L

Methods in molecular biology (Clifton, N.J.)

2013 Volume 1030, Page(s) 407–425

Abstract: Compounds undergoing preclinical development for anti-influenza virus activity require evaluation in small animal models. Laboratory mice are most commonly used for initial studies because of size, cost, and availability. Cotton rats, guinea pigs, and ... ...

Abstract	Compounds undergoing preclinical development for anti-influenza virus activity require evaluation in small animal models. Laboratory mice are most commonly used for initial studies because of size, cost, and availability. Cotton rats, guinea pigs, and ferrets (particularly) have been used for more advanced studies. Each animal infection model has certain limitations relative to human influenza infections. For example, the fever response that is evident in humans only occurs with consistency in ferrets. Mice infected with mouse-adapted viruses and ferrets infected with highly pathogenic avian influenza viruses suffer severe disease, whereas cotton rats and guinea pigs manifest few symptoms. Thus, for each animal model there is a certain set of disease parameters that can be measured. Here we describe methods for assessing the efficacy of anti-influenza virus compounds in each of these animal species.
MeSH term(s)	Animals ; Antiviral Agents/administration & dosage ; Antiviral Agents/pharmacology ; Cell Line ; Disease Models, Animal ; Female ; Ferrets ; Guinea Pigs ; Humans ; Influenza A virus/drug effects ; Influenza A virus/physiology ; Male ; Mice ; Orthomyxoviridae Infections/drug therapy ; Orthomyxoviridae Infections/virology ; Sigmodontinae
Chemical Substances	Antiviral Agents
Language	English
Publishing date	2013
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-62703-484-5_31
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Activities of JNJ63623872 and oseltamivir against influenza A H1N1pdm and H3N2 virus infections in mice.

Smee, Donald F / Barnard, Dale L / Jones, Steven M

Antiviral research

2016 Volume 136, Page(s) 45–50

Abstract: JNJ63623872 (formerly known as VX-787) is an inhibitor of influenza A virus polymerases through interaction with the viral PB2 subunit. This interaction blocks the cap-snatching activity of the virus that is essential for virus replication. Previously ... ...

Abstract	JNJ63623872 (formerly known as VX-787) is an inhibitor of influenza A virus polymerases through interaction with the viral PB2 subunit. This interaction blocks the cap-snatching activity of the virus that is essential for virus replication. Previously published work has documented antiviral activity of JNJ63623872 in cell culture and mouse infection studies. In this report, we extend the in vivo observations by comparing the efficacies of JNJ63623872 and oseltamivir in mice infected with influenza A/California/04/2009 (H1N1pdm) and A/Victoria/3/75 (H3N2) viruses. Animals received JNJ63623872 or oseltamivir orally twice daily for 10 days starting 2 h pre-infection. JNJ63623872 (2, 6, and 20 mg/kg/day) and oseltamivir (20 mg/kg/day) completely prevented death in the H1N1pdm virus infection. Weight loss at nadir was only 12% in mice receiving 2 mg/kg/day of JNJ63623872 compared to 23% and 32%, respectively, in oseltamivir-treated (20 mg/kg/day) and placebo groups. Lung hemorrhage scores, lung weights, and lung virus titers on day 6 were reduced in a dose-responsive manner by JNJ63623872 treatments, whereas oseltamivir treatments were not as effective. JNJ63623872 was less active against H3N2 virus infection, with more body weight loss occurring and only 30% survival at the 2-mg/kg/day dose. Lung scores, lung weights, and H3N2 viral titers in lungs of mice were reduced less by JNJ63623872 treatments compared to the H1N1pdm infection. Nevertheless, the 20-mg/kg/day dose of JNJ63623872 was more effective than oseltamivir (20 mg/kg/day) in improving body weight and reducing the severity of lung infection. JNJ63623872 appears to be an important new drug candidate to treat influenza A H1N1pdm and H3N2 virus infections.
MeSH term(s)	Animals ; Antiviral Agents/therapeutic use ; Drug Discovery ; Drug Therapy, Combination ; Indoles/administration & dosage ; Indoles/therapeutic use ; Influenza A Virus, H1N1 Subtype/drug effects ; Influenza A Virus, H3N2 Subtype/drug effects ; Lung/virology ; Mice ; Orthomyxoviridae Infections/drug therapy ; Orthomyxoviridae Infections/virology ; Oseltamivir/administration & dosage ; Oseltamivir/therapeutic use ; Viral Load/drug effects ; Virus Replication/drug effects
Chemical Substances	Antiviral Agents ; Indoles ; Oseltamivir (20O93L6F9H) ; pimodivir (DFC121MXC3)
Language	English
Publishing date	2016-10-19
Publishing country	Netherlands
Document type	Comparative Study ; Journal Article
ZDB-ID	306628-9
ISSN	1872-9096 ; 0166-3542
ISSN (online)	1872-9096
ISSN	0166-3542
DOI	10.1016/j.antiviral.2016.10.009
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Article ; Online: Strain-dependent disease and response to favipiravir treatment in mice infected with Chikungunya virus.

Julander, Justin G / Dagley, Ashley / Gebre, Makda / Komeno, Takashi / Nakajima, Nozomi / Smee, Donald F / Furuta, Yousuke

Antiviral research

2020 Volume 182, Page(s) 104904

Abstract: Antiviral countermeasures are needed to reduce the morbidity associated with Chikungunya virus (CHIKV) infection. This arbovirus reemerged in 2004 and causes periodic outbreaks in various areas throughout the world. While infection is rarely lethal, the ... ...

Abstract	Antiviral countermeasures are needed to reduce the morbidity associated with Chikungunya virus (CHIKV) infection. This arbovirus reemerged in 2004 and causes periodic outbreaks in various areas throughout the world. While infection is rarely lethal, the majority of people infected with the virus develop a hallmark arthralgia as well as other disease manifestations. The virus is classified within three phylogenetic groups, namely, West African, East/Central/South African (ECSA), and Asian. Six strains of CHIKV covering the three phylogenetic groups were studied for their replication in cell culture, their ability to cause disease in susceptible mouse strains and susceptibility to antiviral treatment. Differential replication kinetics were observed for various CHIKV isolates in cell culture, which coincided with a decreased sensitivity to antiviral treatment as compared with ECSA and Asian clade viruses. This was confirmed in mouse infection studies with severe disease observed in mice infected with West African clade viruses, mild disease phenotype after infection with Asian clade viruses and an intermediate disease severity associated with ECSA virus infection. We also tested a broadly active antiviral, Favipiravir (T-705), which activity was inversely proportional to disease severity. These data suggest that some clades of CHIKV may cause more severe disease and may be more difficult to treat.
MeSH term(s)	Amides/therapeutic use ; Animals ; Antiviral Agents/therapeutic use ; Cell Line ; Chikungunya Fever/drug therapy ; Chikungunya Fever/virology ; Chikungunya virus/classification ; Chikungunya virus/drug effects ; Chikungunya virus/pathogenicity ; Female ; Genotype ; Humans ; Mice ; Mice, Inbred DBA ; Phenotype ; Phylogeny ; Pyrazines/therapeutic use
Chemical Substances	Amides ; Antiviral Agents ; Pyrazines ; favipiravir (EW5GL2X7E0)
Language	English
Publishing date	2020-08-10
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	306628-9
ISSN	1872-9096 ; 0166-3542
ISSN (online)	1872-9096
ISSN	0166-3542
DOI	10.1016/j.antiviral.2020.104904
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