Antiviral Countermeasures Development Center (AC/DC)

抗病毒对策开发中心（AC/DC）

• 批准号: 10513935
• 负责人: George Robert Painter
• 金额: $ 5191.49万
• 依托单位: EMORY UNIVERSITY
• 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/10513935
• 关键词: 2019-nCoV; Acute; Affect; Animal Model; Antiviral Agents; Area; Attention; Back; Biological Availability; Biology; Biotechnology; COVID-19; COVID-19 pandemic; COVID-19 therapeutics; COVID-19 treatment; Chemicals; Contact Tracing; Coronavirus; Data; Development; Diagnostic; Disease; Drug Kinetics; Early Diagnosis; Emergency Situation; Enterovirus; Failure; Family; Family Picornaviridae; Flavivirus; Future; Genome; Genomics; Goals; Health; Heterogeneity; Human; Infrastructure; Interruption; Intervention; Intestinal Absorption; Joints; Knowledge; Lead; Leadership; Lifting; Long COVID; Molecular; Mutation; Neurologic; Oral; Organoids; Orthomyxoviridae; Outpatients; Paramyxovirus; Patients; Performance; Pharmaceutical Chemistry; Pharmacology; Pilot Projects; Polymerase; Population; Program Development; Property; Public Health; RNA; RNA Virus Infections; RNA Viruses; Reporter; Ribonucleosides; Risk; Risk Factors; Route; Safety; Series; Societies; Syndrome; Technical Expertise; Technology; Therapeutic; Togaviridae; Viral; Viral Pathogenesis; Virus; Virus Diseases; Virus Replication; Work; Zoonoses; acute infection; analog; antiviral drug development; betacoronavirus; clinical candidate; clinical development; community transmission; counterscreen; drug candidate; drug development; drug discovery; drug metabolism; experience; global health; high throughput screening; in vivo; inhibitor; innovation; microbiome; molnupiravir; next generation; novel; nucleoside analog; pandemic disease; pathogen; pathogenic virus; personalized medicine; pharmacophore; pre-clinical; preclinical development; prevent; programs; respiratory; response; reverse genetics; risk benefit ratio; small molecule; structural biology; support network; synergism; therapeutic candidate; transmission process; vector-borne; virology

The Antiviral Countermeasures Development Center (AC/DC) will target pathogens in five families of RNA viruses with significant pandemic potential, with the overarching goal to identify and develop orally bioavailable, direct acting antiviral drugs (DAAs). Specific viral targets include zoonotic and human viruses in the coronavirus, paramyxovirus, flavivirus, picornavirus, and togavirus families. The AC/DC MPIs Drs. Painter and Plemper, who will lead this effort, have demonstrated the power of their combined expertise in identifying novel antiviral chemotypes and advancing them from hit stage to clinical candidate, best exemplified by their successful joint work on molnupiravir, considered for emergency approval as the first oral therapeutic for the treatment of COVID- 19. The MPIs have assembled a team of recognized experts in the biology of the viral pathogens being targeted. Their efforts are organized into five synergistic projects supported by cutting-edge technical expertise in five AC/DC scientific cores, covering key areas of preclinical drug discovery and development. A number of the core leaders have significant experience in the development of antivirals in the pharma and biotechnology sectors. The AC/DC will achieve its overarching goal in two major objectives. Pilot studies identified two chemically distinct broad-spectrum ribonucleoside analogs and two non-nucleoside viral polymerase inhibitors with confirmed oral efficacy against one or several of the five viral families targeted, including a novel chemotype that is orally efficacious against SARS-CoV-2 in relevant animal models. Objective 1 will advance this set of four novel DAA leads through final synthetic optimization and de-risking in animal models and primary human organoids as immediate deliverables to mitigate the urgent threat to public health. Simultaneously, Objective 2 will identify additional viable hit chemotypes to expand the AC/DC's antiviral portfolio by leveraging Center expertise in reverse genetics of all viral target families, existing groundbreaking reporter virus technologies, and high-throughput screening under standard and high biocontainment conditions. Hits will be counterscreened against all center target families, molecular viral targets and mechanism of action characterized, and a potency, pharmacokinetics, and pharmacophore-driven synthetic development program launched to identify optimized leads. All data generated by the projects and cores will be evaluated Center-wide utilizing quantitative performance milestones of a defined AC/DC lead advancement cascade that governs the progression of a chemotype from hit to clinical development candidate.

抗病毒对策开发中心(AC/DC)将针对具有重大流行潜力的五种RNA病毒家族的病原体，首要目标是确定和开发口服生物可用、直接作用的抗病毒药物(DAA)。具体的病毒目标包括冠状病毒、副粘病毒、黄病毒、小核糖核酸病毒和TOGA病毒家族中的人畜共患病病毒和人类病毒。AC/DC MPIs的Painter博士和Plemper博士将领导这项工作，他们已经展示了他们的联合专业知识在确定新型抗病毒化学类型以及将它们从热门阶段推广到临床候选药物方面的力量，最好的例子是他们在Molnupiravir方面的成功合作，该药物被认为是第一个被紧急批准用于治疗新冠肺炎的口服疗法。MPIs已经组建了一个由目标病毒病原体的生物学方面的公认专家组成的团队。他们的努力被组织成五个协同项目，由五个AC/DC科学核心的尖端技术专业知识支持，涵盖临床前药物发现和开发的关键领域。一些核心领导者在制药和生物技术部门的抗病毒药物开发方面拥有丰富的经验。交流电/直流电将通过两个主要目标实现其总体目标。初步研究确定了两种化学上不同的广谱核糖核苷类似物和两种非核苷类病毒聚合酶抑制剂，它们对五个目标病毒家族中的一个或几个具有证实的口服疗效，包括一种在相关动物模型中对SARS-CoV-2具有口服疗效的新的化学类型。目标1将通过在动物模型和主要人类有机化合物中进行最终合成优化和降低风险来推进这套四种新的DAA先导化合物，作为立即交付的产品，以减轻对公共健康的紧迫威胁。同时，目标2将确定其他可行的HIT化学类型，通过利用中心在所有病毒目标家族的反向遗传学、现有突破性报告病毒技术以及标准和高生物遏制条件下的高通量筛查方面的专业知识，扩大AC/DC的抗病毒产品组合。HITS将针对所有中心靶标家族、表征的分子病毒靶标和作用机制进行反筛选，并启动效力、药代动力学和药效团驱动的合成开发计划，以确定优化的线索。项目和核心产生的所有数据将在中心范围内进行评估，使用定义的AC/DC导联进步级联的量化性能里程碑，该级联控制化疗类型从HIT到临床开发候选对象的进展。