QCRG Pandemic Response Program

QCRG 流行病应对计划

基本信息

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
项目类别：
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

项目摘要

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个跨学科计划，旨在识别针对 SARS-CoV-2 的新的直接作用抗病毒药物和该提案汇集了来自 14 个不同机构的 45 名研究人员和一个研究小组。合作历史；其中 31 人共同发表了 25 篇关于 SARS-CoV-2,1-25 的论文，为 QCRG 流行病应对计划奠定了坚实的基础。首先，我们将重点关注八项工作。来自八个病毒科的目标类别（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、 Arenaviridae、Nairoviridae 和 Paramyxoviridae），包括七种冠状病毒，重点是 SARS-CoV-2，除了 SARS-CoV-2 RNA（项目 1）之外，我们还将针对病毒 RNA 和 12 种蛋白质。靶向 Nsp3 PLP 和 Nsp5 Mpro 蛋白酶（项目 2）；Nsp3 宏结构域（项目 5）；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）；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。我们还将利用 QCRG 药物发现平台对其他 19 种病毒进行筛选。针对这些目标，包括片段活动、虚拟图书馆对接和高通量屏幕，以发现抑制剂，将通过设计、结构确定和体内测试循环进行优化。将进行药代动力学以及细胞和小鼠感染模型中的活性，然后研究口服生物利用度、清除率、渗透性、溶解度、代谢倾向、毒性和功效。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先导药物（参见合作函）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，我们将利用八个机构提供的一套集成的实验和计算技术生物化学核心将为筛选核心提供纯化的材料，而结构目标和化合物将通过冷冻电镜、冷冻电子断层扫描和晶体学能力来确定蛋白质组学核心中的结构生物学核心将提供机制。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作用。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来测量和优化抗病毒活性。综合建模核心将为结构提供计算支持。整个 QCRG 药物发现平台的测定和抑制剂发现。将提供领导，帮助营造协作环境，并管理指导项目和发展研究项目，将引进新的研究人员。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
作者：
通讯作者：

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.