Antiviral Countermeasures Development Center (AC/DC)

抗病毒对策开发中心（AC/DC）将针对具有重大流行潜力的五个RNA病毒家族中的病原体，其总体目标是鉴定和开发口服生物可利用的直接作用抗病毒药物（DAA）。特异性病毒靶标包括冠状病毒、副粘病毒、黄病毒、小核糖核酸病毒和披膜病毒家族中的人畜共患病毒和人类病毒。将领导这项工作的AC/DC MPI Painter博士和Plemper博士已经证明了他们在识别新型抗病毒化学型并将其从击中阶段推进到临床候选人方面的综合专业知识的力量，最好的例子是他们成功的联合工作莫努匹拉韦，被认为是紧急批准的第一种用于治疗COVID- 19的口服治疗药物。MPI已经组建了一个由被靶向的病毒病原体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领域的抗病毒药物开发方面拥有丰富的经验。AC/DC将在两个主要目标中实现其总体目标。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病毒聚合酶抑制剂，它们对五种目标病毒家族中的一种或几种具有经证实的口服有效性，包括一种在相关动物模型中口服有效对抗SARS-CoV-2的新型化学型。目标1将通过最终的合成优化和降低动物模型和主要人类类器官的风险来推进这一组四种新型DAA先导物，作为立即交付的成果，以减轻对公共卫生的紧迫威胁。同时，目标2将确定其他可行的命中化学型，以扩大AC/DC的抗病毒产品组合，利用中心在所有病毒靶家族的反向遗传学方面的专业知识，现有的突破性报告病毒技术，以及在标准和高生物防护条件下的高通量筛选。将针对所有中心靶标家族、分子病毒靶标和作用机制进行反筛选，并启动效价、药代动力学和药效团驱动的合成开发计划，以确定优化的先导化合物。将使用规定的AC/DC电极导线推进级联的定量性能里程碑在整个中心范围内评价项目和核心生成的所有数据，该级联控制化学型从命中到临床开发候选的进展。

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.