QCRG Pandemic Response Program

QCRG 流行病应对计划

• 批准号: 10512617
• 负责人: Nevan J Krogan
• 金额: $ 6745.2万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10512617
• 关键词: 2019-nCoV; Affinity; Antiviral Agents; Arenavirus; Behavior; Biochemistry; Biological Availability; Biological Sciences; Cell model; Clinical Drug Development; Collaborations; Communicable Diseases; Communication; Complex; Coronavirus; Cryoelectron Microscopy; Crystallography; Development; Docking; Drug Discovery Groups; Drug Kinetics; Environment; Enzymes; Event; Family; Family Picornaviridae; Flaviviridae; Fostering; Foundations; Future; Goals; Head; Immune response; In Vitro; Individual; Infection; Institutes; Institution; Interferons; Investigation; Leadership; Letters; Libraries; Ligands; Mass Spectrum Analysis; Measures; Membrane Proteins; Mentors; Metabolic; Methyltransferase; Modeling; Natural Immunity; Nucleocapsid; Oral; Orthologous Gene; Paper; Paramyxovirus; Peptide Hydrolases; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Polymerase; Process; Property; Protein Methyltransferases; Proteins; Proteomics; Publishing; RNA; RNA Viruses; Recording of previous events; Research; Research Personnel; Research Project Grants; SARS-CoV-2 antiviral; SARS-CoV-2 protease; Scientist; Series; Solubility; Structural Protein; Structure; Techniques; Technology; Testing; Togaviridae; Toxic effect; VDAC1 gene; Viral; Viral Proteins; Virus; Work; adaptive immunity; antiviral drug development; base; career; chemotherapy; clinical candidate; clinical development; collaborative environment; data integration; design; drug discovery; emerging pathogen; high throughput screening; immunoregulation; in vivo; industry partner; inhibitor; innovation; insight; lead optimization; lectures; mouse model; multiple myeloma M Protein; novel; pandemic disease; programs; protein E; response; screening; sharing platform; structural biology; symposium; synergism; viral RNA; virology; virtual library

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.

QCRG流行病应对方案 总体汇总 QCRG（定量生物科学研究所冠状病毒研究小组）大流行应对 该计划是一个跨学科的计划，旨在确定新的SARS-CoV-2直接作用的抗病毒药物， 19其他病毒该提案汇集了来自14个不同机构的45名调查人员， 合作的历史;其中31人共同发表了25篇关于SARS-CoV-2的论文，1 -25项工作， 为QCRG流行病应对计划奠定了坚实的基础。首先，我们将重点放在八个 来自八个病毒科（冠状病毒科，小核糖核酸病毒科，披膜病毒科，黄病毒科，汉坦病毒科， 沙粒病毒科、奈洛病毒科和副粘病毒科），包括7种冠状病毒，重点是SARS-CoV-2， 病毒RNA和12种蛋白质将被靶向。除了SARS-CoV-2 RNA（项目1），我们还将 靶向Nsp 3 PLP和Nsp 5 Mpro蛋白酶（项目2）; Nsp 3宏结构域（项目5）; RdRp 聚合酶，Nsp 7，Nsp 8和Nsp 12（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Nsp 10/16和Nsp 14（项目4）;以及涉及的辅助蛋白 在调节免疫反应，Orf 9 b（项目6）。虽然我们将重点关注SARS-CoV-2，但相关蛋白质 其他19种病毒也将成为目标。使用QCRG药物发现平台，我们将进行筛选 针对这些目标，涉及片段活动、虚拟库对接和高通量筛选，以发现 抑制剂，将使用设计，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以及活性，然后 涉及口服生物利用度、清除率、渗透性、溶解度、代谢倾向、毒性和功效的研究。 每个项目的最终目标是为罗氏的临床开发做好准备的优化电极导线（见 来自传染病主管John Young博士和其他行业合作伙伴的支持。 在整个过程中，我们将利用八个实验和计算技术提供的集成套件， 丹生物化学核心将为筛选核心提供纯化的材料，而 目标和化合物将通过Cryo-EM，Cryo-ET和晶体学能力来确定。 结构生物学核心。蛋白质组学核心中最先进的质谱分析技术将提供 深入了解化合物对其靶点的影响。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， 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抑制剂测定和发现。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。

项目成果

Rapid assembly of SARS-CoV-2 genomes reveals attenuation of the Omicron BA.1 variant through NSP6.

• DOI: 10.1038/s41467-023-37787-0
• 发表时间: 2023-04-21
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Taha, Taha Y.;Chen, Irene P.;Hayashi, Jennifer M.;Tabata, Takako;Walcott, Keith;Kimmerly, Gabriella R.;Syed, Abdullah M.;Ciling, Alison;Suryawanshi, Rahul K.;Martin, Hannah S.;Bach, Bryan H.;Tsou, Chia-Lin;Montano, Mauricio;Khalid, Mir M.;Sreekumar, Bharath K.;Renuka Kumar, G.;Wyman, Stacia;Doudna, Jennifer A.;Ott, Melanie
• 通讯作者: Ott, Melanie

Design and synthesis of naturally-inspired SARS-CoV-2 inhibitors.

自然启发的 SARS-CoV-2 抑制剂的设计和合成。

• DOI: 10.1039/d2md00149g
• 发表时间: 2023
• 期刊: RSC medicinal chemistry
• 影响因子: 4.1
• 作者: Hassan,Haitham;Chiavaralli,Jeanne;Hassan,Afnan;Bedda,Loay;Krischuns,Tim;Chen,Kuang-Yu;Li,AliceShiMing;Delpal,Adrien;Decroly,Etienne;Vedadi,Masoud;Naffakh,Nadia;Agou,Fabrice;Mallart,Sergio;Arafa,ReemK;Arimondo,PaolaB
• 通讯作者: Arimondo,PaolaB

SS148 and WZ16 inhibit the activities of nsp10-nsp16 complexes from all seven human pathogenic coronaviruses.

• DOI: 10.1016/j.bbagen.2023.130319
• 发表时间: 2023-04
• 期刊: Biochimica et biophysica acta. General subjects

Rational Design of Highly Potent SARS-CoV-2 nsp14 Methyltransferase Inhibitors.

• DOI: 10.1021/acsomega.3c02815
• 发表时间: 2023-08-01
• 期刊: ACS OMEGA
• 影响因子: 4.1
• 作者: Stefek, Milan;Chalupska, Dominika;Chalupsky, Karel;Zgarbova, Michala;Dvorakova, Alexandra;Krafcikova, Petra;Li, Alice Shi Ming;Sala, Michal;Dejmek, Milan;Otava, Tomas;Chaloupecka, Ema;Kozak, Jaroslav;Kozic, Jan;Vedadi, Masoud;Weber, Jan;Mertlikova-Kaiserova, Helena;Nencka, Radim
• 通讯作者: Nencka, Radim

Proteases influence colony aggregation behavior in Vibrio cholerae.

• DOI: 10.1016/j.jbc.2023.105386
• 发表时间: 2023-12
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Detomasi, Tyler C.;Batka, Allison E.;Valastyan, Julie S.;Hydorn, Molly A.;Craik, Charles S.;Bassler, Bonnie L.;Marletta, Michael A.
• 通讯作者: Marletta, Michael A.