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.

项目概要/摘要 - 总体 SARS-CoV-2 在持续的未来 RNA 病毒大流行中继续造成严重的发病率和死亡率。 流行病和大流行是不可避免的，迫切需要新的临床试验抗病毒药物。 COVID-19 的大流行潜力进一步强调了尽早在全球范围内提供临床准备的必要性。 除了冠状病毒之外，黄病毒和小核糖核酸病毒也会引起频繁且持续的流行病。 在世界范围内，尚无有效的治疗方法。 对于我们未来的大流行防范至关重要。 人工智能驱动的结构支持抗病毒平台 (ASAP) AViDD 中心将开发新型化学资产 对三个目标病毒家族具有抗病毒活性的 ASAP 将利用最先进的结构。 能够利用人工智能/机器学习和计算化学的最新进展来识别、 尽快启动和实施针对新病毒目标的发现活动是建立在开放原则的基础上的。 科学和快速传播（由专用数据基础设施核心支持）。 ASAP 以成功的 COVID Moonshot 为基础，这是一项开放科学合作，最近筹集了 1100 万美元 来自 Wellcome Trust 通过 WHO Access to COVID Tools Accelerator (ACT-A) 资助临床前研究 开发一种针对主要蛋白酶 (MPro) 的新型口服非共价 SARS-CoV-2 抗病毒药物。 从高通量 X 射线碎片筛选开始，发现团队仅花费了 18 个月和 100 万美元 尽快进入临床前阶段将反映这种快速、经济高效的方法：自动化结构生物学。 Diamond Light Source（Frank von Delft）；PostEra（Alpha Lee）纳米级的 AI/ML 合成模型； Nir London 的化学和共价片段库； Folding@home（John Chodera）；MedChemica（Ed Griffen）领导的工业药物化学团队； 西奈山的抗病毒检测和病毒学专业知识（Kris White；Adolfo García-Sastre ASAP）。 通过新的抗药性靶向方法增强了这个经验丰富的抗病毒发现团队（Karla Kirkegaard 和 Matt Bogyo，斯坦福大学）和深度突变扫描（Jesse Bloom，Fred Hutch）。 得到被忽视疾病药物倡议 (DNDi) (PI Ben Perry) 的支持，以及以下机构的支持信 武田、辉瑞、诺华和 Grupo Insud。 ASAP 影响：ASAP 将成为我们开放科学强大的全球抗病毒发现社区的纽带。 我们的目标是确保全球公平地获得治疗方法，以应对未来的流行病。 产生一个强大的抗病毒管道，包括 3 个新的 I 期候选药物、6 个先导优化 活动、9 个片段到先导活动和 10 个结构支持的强大耐药病毒目标。 相关数据包将加速后续开发和投资。

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

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

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.