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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.
Antiviral Research ( IF 7.6 ) Pub Date : 2018-04-18 , DOI: 10.1016/j.antiviral.2018.04.012
Gregg N Milligan 1 , Mellodee White 2 , Diana Zavala 2 , Richard B Pyles 1 , Vanessa V Sarathy 3 , Alan D T Barrett 4 , Nigel Bourne 1
Affiliation  

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.

中文翻译:

在AG129小鼠模型中针对所有四种登革热病毒血清型的治疗剂的活性测试的频谱:用腺苷核苷抑制剂NITD-008进行的概念验证研究。

登革热是一种由蚊子传播的疾病,对全球公共卫生具有重要意义,它由四种遗传和血清学相关病毒(DENV-1至DENV-4)引起。由于缺乏模仿人类疾病的临床前模型,开发登革热有效疫苗和治疗药物的努力已经减缓。干扰素受体缺陷型AG129小鼠的DENV-2模型是一项重要进展,但仅允许针对单个DENV血清型进行测试。我们使用其他三种DENV血清型的菌株,开发了严重传播的登革热感染的互补AG129小鼠模型。在这里,我们使用腺苷核苷抑制剂NITD-008来表明,这些模型提供了针对DENV血清型全谱在体内进行候选抗病毒药的比较临床前功效测试的能力。
更新日期:2018-04-14
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