QCRG Pandemic Response Program

QCRG大流行应对计划 总体总结 QCRG(定量生物科学研究所冠状病毒研究小组)大流行应对 该计划是一项跨学科计划，旨在为SARS-CoV-2和 19种其他病毒。该提案汇集了一个由来自14个不同机构的45名调查人员组成的团队，他们 合作历史；其中31人共同发表了关于SARS-CoV-2的25篇论文，1-25项努力 为QCRG大流行应对计划奠定了坚实的基础。最初，我们将重点关注八个方面 来自8个病毒科(冠状病毒科、短冠病毒科、托格病毒科、黄病毒科、汉塔病毒科、 包括7种冠状病毒，重点是SARS-CoV-2， 病毒RNA和12种蛋白质将成为目标。除了SARS-CoV-2 RNA(项目1)外，我们还将 以NSP3 PLP和NSP5 MPRO蛋白酶(项目2)；NSP3大结构域(项目5)；RdRp为目标 聚合酶、Nsp7、Nsp8和Nsp12(项目2)结构蛋白E(项目3)、N(项目6)和M (项目3和6)；甲基转移酶Nsp10/16和Nsp14(项目4)；以及所涉及的辅助蛋白 在调节免疫反应方面，Orf9b(项目6)。虽然我们将重点关注SARS-CoV-2相关蛋白 来自其他19种病毒也将成为攻击目标。利用QCRG药物发现平台，我们将进行筛选 在这些目标上，包括碎片活动、虚拟图书馆停靠和高吞吐量屏幕，以发现 抑制剂，将通过设计、结构确定和测试的循环进行优化。体外和体内 将在细胞和小鼠感染模型中进行药代动力学和活性研究，随后将 涉及口服生物利用度、清除度、渗透性、溶解度、代谢性、毒性和有效性的研究。 每个项目的最终目标是为罗氏的临床开发准备一个优化的领导(见Letter of 来自传染病主管John Young博士的支持)和其他行业合作伙伴。 在整个过程中，我们将利用由八家公司提供的一套集成的实验和计算技术 核心。生化核心将为筛选核心提供纯化材料，而 目标和化合物将通过Cryo-EM、Cryo-ET和结晶学能力确定 结构生物学核心。蛋白质组学核心中最先进的质谱学将提供机制 洞察化合物对其目标的影响。药物化学核心将优化有效的- 目标化合物并与体外病毒学核心和体内病毒学核心密切合作，以测量和 优化抗病毒活性。集成建模核心将为结构提供计算支持 在整个QCRG药物发现平台中进行检测和抑制剂发现。行政核心 将提供领导，帮助培养协作环境，并管理指导项目和 发展研究项目，这将带来新的调查人员。

QCRG PANDEMIC RESPONSE PROGRAM OVERALL SUMMARY The QCRG (Quantitative Biosciences Institute Coronavirus Research Group) Pandemic Response Program is an interdisciplinary program that aims to identify new direct-acting antivirals for SARS-CoV-2 and 19 other viruses. The proposal brings together a team of 45 investigators from 14 different institutions with a history of collaboration; 31 of these have co-published together on 25 papers on SARS-CoV-2,1–25 efforts that have laid a strong foundation for the QCRG Pandemic Response Program. Initially, we will focus on eight target classes from eight viral families (Coronaviridae, Picornaviridae, Togaviridae, Flaviviridae, Hantaviridae, Arenaviridae, Nairoviridae and Paramyxoviridae), including seven coronaviruses, with a focus on SARS-CoV-2, where the viral RNA and 12 proteins will be targeted. In addition to the SARS-CoV-2 RNA (Project 1), we will target the Nsp3 PLP and Nsp5 Mpro proteases (Project 2); the Nsp3 macrodomain (Project 5); the RdRp polymerase, Nsp7, Nsp8 and Nsp12 (Project 2) the structural proteins E (Project 3), N (Project 6) and M (Projects 3 and 6); the methyltransferases Nsp10/16 and Nsp14 (Project 4); and the accessory protein involved in regulating the immune response, Orf9b (Project 6). Although we will focus on SARS-CoV-2, related proteins from 19 other viruses will also be targeted. Using the QCRG Drug Discovery Platform, we will perform screens on these targets, involving fragment campaigns, virtual library docking, and high-throughput screens, to discover inhibitors, which will be optimized using cycles of design, structure determination, and testing. In vitro and in vivo pharmacokinetics as well as activity in cellular and mouse models of infection will be carried out, followed by studies involving oral bioavailability, clearance, permeability, solubility, metabolic liabilities, toxicity and efficacy. The final goal of each Project is an Optimized Lead ready for clinical development at Roche (see Letter of Support from Dr. John Young, Head of Infectious Diseases) and other industry partners. Throughout, we will exploit an integrated suite of experimental and computational technologies provided by eight Cores. The Biochemistry Core will provide purified material for the Screening Core, while the structures of targets and compounds will be determined through the Cryo-EM, Cryo-ET and crystallography capabilities of the Structural Biology Core. State-of-the-art mass spectrometry in the Proteomics Core will provide mechanistic insight into the effects of compounds on their targets. The Medicinal Chemistry Core will optimize potent on- target compounds and work closely with the In Vitro Virology Core and In Vivo Virology Core to measure and optimize antiviral activity. The Integrative Modeling Core will provide computational support to structure determination and inhibitor discovery throughout the QCRG Drug Discovery Platform. The Administrative Core will provide leadership, help to foster a collaborative environment, and manage the Mentored Projects and the Developmental Research Projects, which will bring in new investigators.