Spectrum of activity testing for therapeutics against all four dengue virus serotypes in AG129 mouse models

Proof-of-concept studies with the adenosine nucleoside inhibitor NITD-008

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Abstract

Dengue is a mosquito-borne disease of global public health importance caused by four genetically and serologically related viruses (DENV-1 to DENV-4). Efforts to develop effective vaccines and therapeutics for dengue have been slowed by the paucity of preclinical models that mimic human disease. DENV-2 models in interferon receptor deficient AG129 mice were an important advance but only allowed testing against a single DENV serotype. We have developed complementary AG129 mouse models of severe disseminated dengue infection using strains of the other three DENV serotypes. Here we used the adenosine nucleoside inhibitor NITD-008 to show that these models provide the ability to perform comparative preclinical efficacy testing of candidate antivirals in vivo against the full-spectrum of DENV serotypes. Although NITD-008 was effective in modulating disease caused by all DENV serotypes, the variability in protection among DENV serotypes was greater than expected from differences in activity in in vitro testing studies emphasizing the need to undertake spectrum of activity testing to help in prioritization of candidate compounds for further development.

Original languageEnglish (US)
Pages (from-to)104-109
Number of pages6
JournalAntiviral Research
Volume154
DOIs
StatePublished - Jun 1 2018

Fingerprint

Dengue Virus
Nucleosides
Adenosine
Dengue Vaccines
Interferon Receptors
Severe Dengue
Therapeutics
Dengue
Culicidae
Antiviral Agents
Public Health
Serogroup
Viruses
Infection

Keywords

  • Animal model
  • Antiviral testing
  • Dengue virus
  • Flavivirus
  • Preclinical development

ASJC Scopus subject areas

  • Pharmacology
  • Virology

Cite this

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title = "Spectrum of activity testing for therapeutics against all four dengue virus serotypes in AG129 mouse models: Proof-of-concept studies with the adenosine nucleoside inhibitor NITD-008",
abstract = "Dengue is a mosquito-borne disease of global public health importance caused by four genetically and serologically related viruses (DENV-1 to DENV-4). Efforts to develop effective vaccines and therapeutics for dengue have been slowed by the paucity of preclinical models that mimic human disease. DENV-2 models in interferon receptor deficient AG129 mice were an important advance but only allowed testing against a single DENV serotype. We have developed complementary AG129 mouse models of severe disseminated dengue infection using strains of the other three DENV serotypes. Here we used the adenosine nucleoside inhibitor NITD-008 to show that these models provide the ability to perform comparative preclinical efficacy testing of candidate antivirals in vivo against the full-spectrum of DENV serotypes. Although NITD-008 was effective in modulating disease caused by all DENV serotypes, the variability in protection among DENV serotypes was greater than expected from differences in activity in in vitro testing studies emphasizing the need to undertake spectrum of activity testing to help in prioritization of candidate compounds for further development.",
keywords = "Animal model, Antiviral testing, Dengue virus, Flavivirus, Preclinical development",
author = "Gregg Milligan and Mellodee White and Diana Zavala and Richard Pyles and Vanessa Sarathy and Alan Barrett and Nigel Bourne",
year = "2018",
month = "6",
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doi = "10.1016/j.antiviral.2018.04.012",
language = "English (US)",
volume = "154",
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T1 - Spectrum of activity testing for therapeutics against all four dengue virus serotypes in AG129 mouse models

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AU - Milligan, Gregg

AU - White, Mellodee

AU - Zavala, Diana

AU - Pyles, Richard

AU - Sarathy, Vanessa

AU - Barrett, Alan

AU - Bourne, Nigel

PY - 2018/6/1

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N2 - Dengue is a mosquito-borne disease of global public health importance caused by four genetically and serologically related viruses (DENV-1 to DENV-4). Efforts to develop effective vaccines and therapeutics for dengue have been slowed by the paucity of preclinical models that mimic human disease. DENV-2 models in interferon receptor deficient AG129 mice were an important advance but only allowed testing against a single DENV serotype. We have developed complementary AG129 mouse models of severe disseminated dengue infection using strains of the other three DENV serotypes. Here we used the adenosine nucleoside inhibitor NITD-008 to show that these models provide the ability to perform comparative preclinical efficacy testing of candidate antivirals in vivo against the full-spectrum of DENV serotypes. Although NITD-008 was effective in modulating disease caused by all DENV serotypes, the variability in protection among DENV serotypes was greater than expected from differences in activity in in vitro testing studies emphasizing the need to undertake spectrum of activity testing to help in prioritization of candidate compounds for further development.

AB - Dengue is a mosquito-borne disease of global public health importance caused by four genetically and serologically related viruses (DENV-1 to DENV-4). Efforts to develop effective vaccines and therapeutics for dengue have been slowed by the paucity of preclinical models that mimic human disease. DENV-2 models in interferon receptor deficient AG129 mice were an important advance but only allowed testing against a single DENV serotype. We have developed complementary AG129 mouse models of severe disseminated dengue infection using strains of the other three DENV serotypes. Here we used the adenosine nucleoside inhibitor NITD-008 to show that these models provide the ability to perform comparative preclinical efficacy testing of candidate antivirals in vivo against the full-spectrum of DENV serotypes. Although NITD-008 was effective in modulating disease caused by all DENV serotypes, the variability in protection among DENV serotypes was greater than expected from differences in activity in in vitro testing studies emphasizing the need to undertake spectrum of activity testing to help in prioritization of candidate compounds for further development.

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KW - Dengue virus

KW - Flavivirus

KW - Preclinical development

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