Targeting STT3A and STT3B to Block Flavivirus Replication

摘要： 蚊子传播的黄病毒在世界范围内引起疾病，其成员如登革热病毒（DENV），寨卡病毒（Zika） 寨卡病毒（ZIKV）和西尼罗河病毒（WNV）每年感染超过1亿人。的可用性 因此，减少黄病毒感染小分子抗病毒药物可具有立即和显著的 对公共卫生计划的影响，这些计划旨在改善感染西尼罗河病毒、登革病毒 还有ZIKV最近，使用插入诱变或CRISPR-Cas9的全基因组筛选 敲除方法已经鉴定了寡糖基转移酶（OST）的亚基，特别是STT 3A和 STT 3B，作为黄病毒生命周期的必需品。使用新的生物发光报告物的药物发现努力 检测OST功能抑制的方法最近也成功地鉴定了新的小的 分子靶向OST [13]。这类抑制剂直接与STT 3A和STT 3B结合 亚基，因此具有成为用于治疗黄病毒感染的抗病毒剂的潜力。的 一项拟议的研究试图在结构上优化这种药物样小分子的效力和溶解度 系列，以推进这种治疗策略的临床前测试。

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.