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首页> 外文期刊>Antiviral chemistry & chemotherapy >Small molecule pan-dengue and West Nile virus NS3 protease inhibitors.
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Small molecule pan-dengue and West Nile virus NS3 protease inhibitors.

机译：小分子泛登革热和西尼罗河病毒NS3蛋白酶抑制剂。

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BACKGROUND: Dengue fever, dengue haemorrhagic fever, and dengue shock syndrome are caused by infections with any of the four serotypes of the dengue virus (DENV), and are an increasing global health risk. The related West Nile virus (WNV) causes significant morbidity and mortality as well, and continues to be a threat in endemic areas. Currently no FDA-approved vaccines or therapeutics are available to prevent or treat any of these infections. Like the other members of Flaviviridae, DENV and WNV encode a protease (NS3) which is essential for viral replication and therefore is a promising target for developing therapies to treat dengue and West Nile infections. METHODS: Flaviviral protease inhibitors were identified and biologically characterized for mechanism of inhibition and DENV antiviral activity. RESULTS: A guanidinylated 2,5-dideoxystreptamine class of compounds was identified that competitively inhibited the NS3 protease from DENV(1-4) and WNV with 50% inhibitory concentration values in the 1-70 muM range. Cytotoxicity was low; however, antiviral activity versus DENV-2 on VERO cells was not detectable. CONCLUSIONS: This class of compounds is the first to demonstrate competitive pan-dengue and WNV NS3 protease inhibition and, given the sequence conservation among flavivirus NS3 proteins, suggests that developing a pan-dengue or possibly pan-flavivirus therapeutic is feasible.
机译：背景：登革热，登革出血热和登革热休克综合征是由登革病毒的四种血清型中的任何一种感染引起的，并且正在增加全球健康风险。相关的西尼罗河病毒（WNV）也会引起很大的发病率和死亡率，并且继续是流行地区的威胁。目前，尚无FDA批准的疫苗或治疗剂可用于预防或治疗这些感染。与黄病毒科的其他成员一样，DENV和WNV编码一种蛋白酶（NS3），该酶对于病毒复制至关重要，因此是开发治疗登革热和西尼罗河感染的疗法的有希望的目标。方法：鉴定黄病毒蛋白酶抑制剂并对其生物学特性进行抑制机制和DENV抗病毒活性的表征。结果：鉴定出一种胍基化的2,5-二脱氧链胺胺类化合物，其竞争性抑制DENV（1-4）和WNV的NS3蛋白酶，其50％抑制浓度在1-70μM范围内。细胞毒性低;但是，未检测到针对VERV细胞的抗DENV-2抗病毒活性。结论：这类化合物是第一个证明具有竞争性的泛登革热和WNV NS3蛋白酶抑制作用的化合物，考虑到黄病毒NS3蛋白之间的序列保守性，这表明开发泛登革热或可能的泛黄病毒治疗剂是可行的。

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