Targeting STT3A and STT3B to Block Flavivirus Replication

靶向 STT3A 和 STT3B 阻止黄病毒复制

• 批准号: 9409492
• 负责人: Michael Christopher Van Zandt
• 金额: $ 29.87万
• 依托单位: NEW ENGLAND DISCOVERY PARTNERS, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-16 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9409492
• 关键词: Affect; Antiviral Agents; CRISPR/Cas technology; Chemicals; Clinical; Collaborations; Culicidae; Dengue; Dengue Virus; Development; Disease; Drug Kinetics; Evaluation; Flavivirus; Flavivirus Infections; Goals; Individual; Infection; Insertional Mutagenesis; Knock-out; Lead; Life Cycle Stages; Link; Measures; Metabolic; Methods; Molecular Target; Morbidity - disease rate; Outcome; Pharmaceutical Preparations; Phase; Population; Preclinical Testing; Property; Proteins; Public Health; Reporter; Research; Series; Small Business Technology Transfer Research; Solubility; Structure-Activity Relationship; Techniques; Therapeutic; Viral; West Nile virus; Yellow fever virus; Zika Virus; analog; chemical synthesis; combinatorial; drug discovery; genome-wide analysis; glycosylation; high throughput screening; improved; improved outcome; in vivo; inhibitor/antagonist; member; mortality; novel; paralogous gene; programs; small molecule; small molecule inhibitor; success

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.

抽象的： 蚊媒黄病毒在世界范围内引起疾病，其中包括登革热病毒 (DENV)、寨卡病毒 病毒（ZIKV）和西尼罗病毒（WNV）每年感染超过 1 亿人。的可用性 因此，减少黄病毒感染的小分子抗病毒药物可能会产生立竿见影的效果。 对旨在改善西尼罗河病毒、登革热病毒、登革热病毒感染人群的结果的公共卫生计划的影响 和寨卡病毒。最近，使用插入突变或 CRISPR-Cas9 进行全基因组筛选 敲除方法已鉴定出寡糖转移酶 (OST) 的亚基，特别是 STT3A 和 STT3B，对于黄病毒生命周期至关重要。使用新型生物发光报告基因进行药物发现工作 检测 OST 功能抑制的方法最近也取得了成功，鉴定了新型小分子 靶向 OST 的分子 [13]。此类抑制剂直接与 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剂。这 拟议的研究旨在从结构上优化这种药物样小分子的效力和溶解度 系列，以推进这种临床前测试的治疗策略。