Midwest AViDD Center

项目5-大流行病毒解旋酶抑制剂 摘要 该项目的目标是开发针对病毒解旋酶的泛家族抗病毒候选药物， 冠状病毒和黄病毒。所有优先RNA病毒在其基因组中编码病毒解旋酶结构域，并且它们 在结构和生化特征上具有高度的相似性。病毒RNA解旋酶是病毒RNA解旋酶的关键组分， 复制酶复合物，并为RNA病毒复制所必需。此外，它显示出与DNA序列的高序列同源性。 病毒家族（例如，在SARS 2内100%同一性）。因此，病毒RNA解旋酶可以作为一种新的 RNA病毒的抗病毒靶点，具有高耐药性屏障。在过去的10年里， 为开发针对甲病毒解旋酶结构域的抗病毒药做出了重大贡献 （nsP2）和经验证的病毒解旋酶作为可用于开发有效的抗病毒药物。基于这一成功，我们 假设病毒解旋酶可以作为安全有效的抗SARS 2和其他病毒药物的有效靶点， 优先RNA病毒。 在这里，我们提出了一个全面的抗病毒发现运动，目标是病毒解旋酶与多学科 结合超高通量筛选和DNA编码化学技术， 强大的命中验证计划与抗病毒测试，结构生物学和生物化学方法（目标1）。 此外，我们建议通过命中-先导开发来推进有希望的病毒解旋酶抑制剂命中， 经验证的线索作为药物开发候选药物，药物化学与基于AI的药物设计相结合， DMPK研究和体内抗病毒功效研究（目的2）。最后，我们将提供1 - 2口服生物利用度， 可申请专利的、类似药物的IND激活的小分子（开发候选者+备份），非常适合 由制药合作伙伴翻译（目标3）。我们发现了一种新的热门化合物 （UNC0379），其具有抗SARS 2活性（核心B）。pi和 已建立的团队（Chung，病毒学/PI;班尼斯特，医学化学/副;斯派塞，uHTS; Luo， 病毒复制酶; Raney，解旋酶生物化学）协同地联合收割机抗病毒药物发现（Head-Gordon， Compchem/AI）具有优异的核心支持（核心B和核心C）。我们的努力将提供新的直接类 解旋酶靶向抗病毒剂，用于SARS 2感染和其他高优先级病毒病原体。

Project 5 – Pandemic Virus Helicase Inhibitors ABSTRACT The goal of this project is to develop pan-family, antiviral drug candidates targeting the viral helicase of coronavirus and flavivirus. All priority RNA viruses encode a viral helicase domain in their genomes, and they share high similarity in structure and biochemical features. Viral RNA helicase is a critical component of the viral replicase complex and is essential for RNA virus replication. Further, it shows a high sequence homology within the virus family (e.g., 100% identity within SARS2). Consequently, viral RNA helicases can serve as a novel antiviral target for RNA viruses with a high barrier to drug resistance. During the past 10 years, the Chung lab has made significant contributions to the development of antivirals targeting the alphavirus helicase domain (nsP2) and validated viral helicase as druggable for developing potent antivirals. Based on this success, we hypothesize the viral helicase can serve as a valid target for safe and effective antivirals for SARS2 and other priority RNA viruses. Here, we propose a comprehensive antiviral discovery campaign targeting viral helicase with a multi-disciplinary approach combining ultra-high-throughput screening and DNA-Encoded Chemistry Technology followed by a robust hit validation scheme with antiviral testing, structural biology, and biochemical approaches (Aim 1). Further, we propose to advance promising viral helicase inhibitor hits through hit-to-lead development, giving validated leads as drug development candidates with medicinal chemistry paired with AI-based drug design, DMPK studies, and in vivo antiviral efficacy studies (Aim 2). Finally, we will deliver 1-2 orally bioavailable, patentable, druglike IND-enabled small molecules (a development candidate + backup) that are well-suited for translation by a pharma partner (Aim 3). Our proposal is supported by our discovery of a novel hit compound (UNC0379) with an anti-SARS2 activity from a pilot 100,000-compound library screen (Core B). The PI and established team (Chung, virology/PI; Bannister, Med. Chem/deputy; Spicer, uHTS; Luo, structural biology of viral replicase; Raney, helicase biochemistry) synergistically combine antiviral drug discovery (Head-Gordon, Compchem/AI) with excellent core support (Core B and Core C). Our effort will deliver new classes of direct helicase-targeting antiviral agents for SARS2 infection and other high priority viral pathogens.