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）将针对五种具有巨大大流行潜力的RNA病毒家族的病原体，其总体目标是识别和开发口服可生物可利用的直接作用，直接作用抗病毒药（DAAS）。特定的病毒靶标包括冠状病毒，帕马氏病毒，黄素病毒，picornavirus和togavirus家族中的人畜共患病和人类病毒。 AC/DC MPIS DRS。将领导这项努力的画家和佩珀（Painter and Plemper）证明了他们在识别新型抗病毒化学型和从命中阶段发展到临床候选者的共同专业知识的力量，最好地说明了他们在Molnupiravir上的成功合作，被认为是紧急批准的联合批准，是为了治疗COVID-19的第一个口头疗法。目标。他们的努力被组织成五个协同的项目，并由五个AC/DC科学核心的尖端技术专长支持，涵盖了临床前药物发现和开发的关键领域。许多核心领导者在制药和生物技术领域的抗病毒药物发展方面具有丰富的经验。 AC/DC将在两个主要目标中实现其总体目标。试验研究确定了两种化学不同的宽光谱核糖核苷类似物和两个非核苷病毒聚合酶抑制剂，对靶向的五个病毒家族中的一个或几个具有确认的口服疗效，包括针对靶向的五个病毒家族，包括一种新型的化学型，在相关动物模型中针对SARS-COV-COV具有口服有效性。目标1将通过最终的合成优化和在动物模型和原代人体器官中的最终合成优化和降低风险来推动这组四个新颖的​​DAA，作为立即可交付成果，以减轻对公共卫生的紧急威胁。同时，目标2将通过利用中心专业知识来确定其他可行的HIT化学型，以扩大AC/DC的抗病毒投资组合，以在所有病毒靶标家族的反向遗传学，现有的突破性报告病毒技术以及在标准和高生物关注条件下进行高通量筛查。在所有中心目标家族，分子病毒靶标和作用机理以及效力，药代动力学以及药体驱动的合成发展计划中，将对所有中心靶标系列，分子病毒靶标和作用机理进行反屏幕进行反映。这些项目和核心生成的所有数据将通过定义的AC/DC铅铅级别级联级联对中心范围进行评估，该级联控制了化学型从HIT到临床开发候选者的发展。