Targeting STT3A and STT3B to Block Flavivirus Replication

摘要： 蚊媒黄病毒在全球范围内引发疾病，成员包括登革热病毒(DENV)、寨卡病毒 病毒(ZIKV)和西尼罗河病毒(WNV)每年感染1亿多人。是否可以使用 因此，减少黄病毒感染的小分子抗病毒药物可能会立即和实质性地 对公共卫生项目的影响，这些项目旨在改善感染西尼罗河病毒、登革热病毒、 和ZIKV。最近，使用插入突变或CRISPR-Cas9进行全基因组筛选 基因敲除方法已经确定了寡糖转移酶(OST)的亚基，特别是STT3A和 STT3B是黄病毒生命周期所必需的。利用一种新型生物发光记者进行药物发现 检测OST功能抑制的研究最近也在鉴定新的Small方面取得了成功 靶向OST的分子[13]。这类抑制剂直接与STT3A和STT3B结合 亚基，因此有可能成为治疗黄病毒感染的抗病毒药物。这个 拟议的研究试图从结构上优化这种类药物小分子的效力和溶解性。 系列，以推进这一临床前试验的治疗策略。

Abstract: Mosquito-borne flaviviruses cause disease worldwide, with members such as dengue virus (DENV), Zika virus (ZIKV) and west nile virus (WNV) infecting more than 100 million individuals annually. The availability of small molecule antivirals that reduce flavivirus infection therefore could have an immediate and substantial impact on public health programs that seek to improve outcomes for populations infected with WNV, DENV, and ZIKV. Recently, genome-wide screening using either insertional mutagenesis or CRISPR-Cas9 knockout approaches have identified subunits of the oligosaccharyltransferase (OST), specifically STT3A and STT3B, as essential for the flavivirus life cycle. Drug discovery efforts using a novel bioluminescent reporter that detects inhibition of OST function have also had recent success with the identification of novel small molecules that target the OST [13]. This class of inhibitors directly engage with the STT3A and STT3B subunits and therefore have the potential to be antiviral agents for the treatment of flavivirus infection. The proposed research seeks to structurally optimize the potency and solubility of this drug-like small molecule series in order to advance this therapeutic strategy for preclinical testing.