AI-driven Structure-enabled Antiviral Platform (ASAP)

人工智能驱动的结构支持抗病毒平台 (ASAP)

• 批准号: 10513865
• 负责人: John Damon Chodera
• 金额: $ 6767.39万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 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/10513865
• 关键词: 2019-nCoV; Antiviral Agents; Biological Assay; COVID-19; Chemicals; Chemistry; Clinic; Clinical Trials; Collaborations; Communities; Coronavirus; Data; Development; Diamond; Disease; Ensure; Epidemic; Family; Family Picornaviridae; Flavivirus; Free Energy; Funding; Future; Home; Industrialization; Investments; Lead; Letters; Libraries; Light; London; Modeling; Morbidity - disease rate; Oral; Peptide Hydrolases; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; RNA Viruses; Resistance; Roentgen Rays; SARS-CoV-2 antiviral; Seasons; Secure; Source; Structure; Technology; Therapeutic; Trust; Viral; combat; computational chemistry; coronavirus disease; cost efficient; data infrastructure; lead optimization; mortality; mutation screening; nanoscale; neglect; novel; novel strategies; open data; pandemic disease; pandemic preparedness; pre-clinical; preclinical development; structural biology; therapeutically effective; tool; virology

PROJECT SUMMARY/ABSTRACT - Overall SARS-CoV-2 continues to cause severe morbidity and mortality in the ongoing pandemic. Future RNA virus epidemics and pandemics are inevitable. New clinical-trial-ready antivirals are urgently needed RNA viruses of pandemic potential. COVID-19 has further underscored the need for early, global access to clinic-ready compounds. Beyond coronaviruses; flaviviruses and picornaviruses also cause frequent and ongoing epidemics worldwide and have no effective therapeutics. Maintaining a portfolio of novel, clinic-ready therapeutics are critical for our future pandemic preparedness. The AI-driven Structure-enabled Antiviral Platform (ASAP) AViDD Center will develop novel chemical assets that have antiviral activity against three target viral families. ASAP will leverage state-of-the-art structure-enabled technologies capable of leveraging recent advances in AI/ML and computational chemistry in identifying, enabling, and prosecuting discovery campaigns against novel viral targets. ASAP is built on principles of open science and rapid dissemination (enabled by a dedicated Data Infrastructure Core). ASAP builds on the successful COVID Moonshot, an open science collaboration that recently secured $11 million from the Wellcome Trust via the WHO Access to COVID Tools Accelerator (ACT-A) to fund preclinical development of a novel oral noncovalent SARS-CoV-2 antiviral acting against the main protease (MPro). Beginning with a high-throughput X-ray fragment screen, the discovery team spent just 18 months and $1M to reach the preclinical phase. ASAP will mirror this rapid, cost-efficient approach: automated structural biology at Diamond Light Source (Frank von Delft); AI/ML synthesis models from PostEra (Alpha Lee); nanoscale chemistry and covalent fragment libraries from Nir London; massively distributed free energy calculations on Folding@home (John Chodera); an industrial medicinal chemistry team led by MedChemica (Ed Griffen); and antiviral assays and virology expertise at Mount Sinai (Kris White; Adolfo García-Sastre). ASAP augments this seasoned antiviral discovery team with new approaches to resistance-robust targeting (Karla Kirkegaard and Matt Bogyo, Stanford) and deep mutational scanning (Jesse Bloom, Fred Hutch). ASAP is supported by the Drugs for Neglected Diseases Initiative (DNDi) (PI Ben Perry), and Letters of Support from Takeda, Pfizer, Novartis, and Grupo Insud. ASAP Impact: ASAP will become the nexus of a robust global antiviral discovery community. Our open science approach focuses on ensuring global, equitable access to therapeutics to combat future pandemics. We aim to produce a robust antiviral pipeline consisting of 3 new Phase I ready candidates, 6 lead optimization campaigns, 9 fragment-to-lead campaigns, and 10 structure-enabled resistance-robust viral targets. Our associated data packages will accelerate follow-on development and investment.

项目总结/摘要-总体 SARS-CoV-2在目前的大流行中继续造成严重的发病率和死亡率。未来RNA病毒 流行病和大流行病是不可避免的。新的临床试验准备抗病毒药物是急需的RNA病毒， 大流行的可能性。COVID-19进一步强调了尽早在全球范围内获得临床准备就绪的必要性 化合物.除了冠状病毒，黄病毒和小核糖核酸病毒也会引起频繁和持续的流行病 世界范围内，没有有效的治疗方法。保持一个新的，临床准备的治疗组合是 对我们未来的大流行防范至关重要。 人工智能驱动的结构使能抗病毒平台（ASAP）AViDD中心将开发新型化学资产 对三种目标病毒家族具有抗病毒活性。ASAP将利用最先进的结构化 技术能够利用AI/ML和计算化学的最新进展， 启动和开展针对新病毒靶点的发现活动。ASAP建立在开放的原则之上 科学和快速传播（通过专用的数据基础设施核心实现）。 ASAP以成功的COVID Moonshot为基础，这是一项开放科学合作，最近获得了1100万美元的资金 通过世卫组织获取新冠病毒工具加速器（ACT-A）从惠康信托基金获得资金， 开发一种新的口服非共价SARS-CoV-2抗病毒药物，作用于主要蛋白酶（MPro）。 从高通量的X射线碎片筛选开始，发现团队只花了18个月和100万美元， 达到临床前阶段。ASAP将反映这种快速，具有成本效益的方法：自动结构生物学， 金刚石光源（Frank von德尔夫特）; PostEra的AI/ML合成模型（Alpha Lee）;纳米级 Nir伦敦的化学和共价片段库; Folding@home（John Chodera）;由MedChemica（艾德格里芬）领导的工业药物化学团队; 以及西奈山的抗病毒检测和病毒学专业知识（克里斯白色;阿道夫·加西亚-萨斯特雷）。ASAP 用新的方法增强这个经验丰富的抗病毒发现团队的抵抗力-强大的靶向（卡拉 Kirkegaard和Matt Bogyo，斯坦福大学）和深度突变扫描（Jesse Bloom，Fred Hutch）。ASAP是 由被忽视疾病药物计划（DNDi）（PI Ben佩里）支持，以及来自 武田、辉瑞、诺华和Insud集团。 ASAP影响：ASAP将成为强大的全球抗病毒发现社区的纽带。我们的开放科学 这一方法的重点是确保全球公平获得治疗药物，以防治未来的大流行病。我们的目标 生产一个强大的抗病毒产品线，包括3个新的I期候选药物，6个先导优化药物， 活动，9个片段到铅活动，和10个结构使能耐药性强大的病毒靶标。我们 相关数据包将加快后续开发和投资。

项目成果

An in-solution snapshot of SARS-COV-2 main protease maturation process and inhibition.

• DOI: 10.1038/s41467-023-37035-5
• 发表时间: 2023-03-20
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Noske, Gabriela Dias;Song, Yun;Fernandes, Rafaela Sachetto;Chalk, Rod;Elmassoudi, Haitem;Koekemoer, Lizbe;Owen, C. David J.;El-Baba, Tarick V.;Robinson, Carol;Oliva, Glaucius;Godoy, Andre Schutzer
• 通讯作者: Godoy, Andre Schutzer

Allosteric regulation and crystallographic fragment screening of SARS-CoV-2 NSP15 endoribonuclease.

• DOI: 10.1093/nar/gkad314
• 发表时间: 2023-06-09
• 期刊: NUCLEIC ACIDS RESEARCH
• 影响因子: 14.9
• 作者: Godoy, Andre Schutzer;Nakamura, Aline Minalli;Douangamath, Alice;Song, Yun;Noske, Gabriela Dias;Gawriljuk, Victor Oliveira;Fernandes, Rafaela Sachetto;Pereira, Humberto D. Muniz;Oliveira, Ketllyn Irene Zagato;Fearon, Daren;Dias, Alexandre;Krojer, Tobias;Fairhead, Michael;Powell, Alisa;Dunnet, Louise;Brandao-Neto, Jose;Skyner, Rachael;Chalk, Rod;Bajusz, David;Bege, Miklos;Borbas, Aniko;Keseru, Gyoergy Miklos;von Delft, Frank;Oliva, Glaucius
• 通讯作者: Oliva, Glaucius

Accelerating antiviral drug discovery: lessons from COVID-19.

• DOI: 10.1038/s41573-023-00692-8
• 发表时间: 2023-07
• 期刊: NATURE REVIEWS DRUG DISCOVERY
• 影响因子: 120.1
• 作者: von Delft, Annette;Hall, Matthew D.;Kwong, Ann D.;Purcell, Lisa A.;Saikatendu, Kumar Singh;Schmitz, Uli;Tallarico, John A.;Lee, Alpha A. A.
• 通讯作者: Lee, Alpha A. A.

Differential inhibition of intra- and inter-molecular protease cleavages by antiviral compounds.

• DOI: 10.1128/jvi.00928-23
• 发表时间: 2023-12-21
• 期刊: JOURNAL OF VIROLOGY
• 影响因子: 5.4
• 作者: Doherty, Jennifer S.;Kirkegaard, Karla
• 通讯作者: Kirkegaard, Karla