Center for Antiviral Medicines & Pandemic Preparedness (CAMPP)

摘要 正在进行的新冠肺炎大流行暴露出迫切需要加强治疗准备 应对未来的病毒暴发和大流行。“抗病毒药物和研究中心”的总体目标 预防大流行“(CAMPP)因此是为了制定新的战略和加强药物发现 针对引起大流行关注的RNA病毒的直接作用抗病毒药物的管道。CAMPP的具体重点将是 将开发针对冠状病毒SARS-CoV-2(SCV2)、SARS和MERS的抗病毒药物；黄病毒包括 寨卡病毒、西尼罗河病毒和登革热病毒；以及出血热病毒，包括丝状病毒埃博拉和布尼亚病毒 严重发热伴血小板减少综合征病毒和拉萨病毒。这些病原体中的任何一种感染都有 可能导致严重的人类疾病，死亡率很高，目前有抗病毒的选择 治疗是有限的。抗病毒药物雷米地韦和几种单抗治疗已经收到 用于治疗新冠肺炎的紧急使用授权，聚合酶抑制剂莫努普拉韦由 默克公司预计将在不久的将来获得EUA。单抗也可用于治疗埃博拉病毒 然而，这些药物都不能口服，这给治疗带来了额外的挑战。 早期感染。目前还没有针对CAMPP黄病毒和出血热病毒的批准治疗方法。 为此，我们组建了一支世界级的多学科调查团队，他们具有以下专业知识 相关病毒的病毒学、结构和计算生物学、化学蛋白质组学、药理学和 有机/动物模型，将与药物发现部门的药物开发专家密切合作 卡利布尔斯克里普斯研究所，以进一步开发四大类有前景的资产 在我们的药物研发流程中。首先，我们建议开发一种潜在的同类最好的口服生物利用度 冠状病毒蛋白酶(CLPro)抑制剂，用于包括SCV2在内的冠状病毒，来自正在接受治疗的晚期药物资产 ADME优化，预计将在未来三年内进入支持IND的研究。第二，我们将 确定和优化针对SCV2和其他CAMPP病毒的RNA聚合酶抑制剂，目标是达到 在未来四年内支持IND的研究。我们建议的第三个重点是开发抗病毒药物 其他由SCV2和其他构成大流行威胁的病毒编码的“可用药”蛋白质；这些资产 包括SCV2解旋酶、E蛋白编码离子通道活性、进入和融合活性的抑制物，以及 核衣壳，目的是为这些中期资产的子集获得体内概念验证。最后， 我们建议以传统上被认为是无法下药的非酶蛋白为目标，包括SCV2和黄病毒 结构蛋白质和RNA结构，以开发抗病毒药物开发的新策略。CAMPP 提供由调查人员、专业知识以及外部制药和基金组成的高度集成的基础设施 将确保中心成功实现我们的目标和应对药物挑战的合作伙伴 发现过程。

SUMMARY The ongoing COVID-19 pandemic has brought to light an urgent need to enhance the therapeutic preparedness for future viral outbreaks and pandemics. The overarching goal of the “Center for Antiviral Medicines & Pandemic Preparedness” (CAMPP) is thus to develop novel strategies and enhance the drug discovery pipelines for direct-acting antivirals against RNA viruses of pandemic concern. The specific focus of CAMPP will be to develop antivirals against coronaviruses SARS-CoV-2 (SCV2), SARS and MERS; flaviviruses including Zika, West Nile and Dengue virus; and hemorrhagic fever viruses including the filovirus Ebola, and bunyaviruses Severe fever with thrombocytopenia syndrome virus and Lassa virus. Infection by any of these agents has the potential to cause severe human disease with significant mortality rates and current options for antiviral treatments are limited. The antiviral drug remdesivir and several monoclonal antibody treatments have received emergency use authorization (EUA) for treatment of COVID-19, and the polymerase inhibitor molnupiravir by Merck is expected to be granted EUA in the near future. Monoclonal antibodies are also available to treat Ebola virus infection, however, none of these drugs can be administered orally, posing additional challenges in treating early infection. There are no approved treatments for the CAMPP flaviviruses and hemorrhagic fever viruses. Toward this end, we have assembled a world class multidisciplinary team of investigators with expertise in virology of relevant viruses, structural and computational biology, chemoproteomics, pharmacology and organoid/animal models, who will work closely with the drug development experts at the drug discovery division of The Scripps Research Institute, Calibr, to further the development of four major classes of promising assets in our drug discovery pipeline. First, we propose to develop a potentially best-in-class, orally bioavailable coronavirus protease (CLpro) inhibitor for coronaviruses including SCV2, from a late-stage drug asset undergoing ADME optimization that is expected to enter IND-enabling studies within the next three years. Second, we will identify and optimize RNA polymerase inhibitors for SCV2 and other CAMPP viruses, with the goal of reaching IND-enabling studies within the next four years. The third focus of our proposal is to develop antivirals against other ‘druggable’ proteins encoded by SCV2 and additional viruses posing a pandemic threat; these assets include inhibitors of SCV2 helicase, E-protein encoded ion channel activity, entry and fusion activities, and nucleocapsid, with the goal of obtaining in vivo proof-of-concept for a subset of these mid-stage assets. Finally, we propose to target traditionally considered ‘undruggable’ non-enzymatic proteins including SCV2 and flaviviral structural proteins as well as RNA structure, to develop novel strategies for antiviral drug development. CAMPP provides a highly integrated infrastructure of investigators, expertise and external pharmaceutical and founding partners that will ensure the Center’s success in achieving our goals and navigating challenges of the drug discovery process.