Center for Antiviral Medicines & Pandemic Preparedness (CAMPP)

总结 持续的COVID-19大流行揭示了加强治疗准备的迫切需要 为未来的病毒爆发和流行做准备。“抗病毒药物和治疗中心”的总体目标是： 因此，“大流行准备”（CAMPP）旨在开发新的策略并促进药物发现 针对大流行性RNA病毒的直接作用抗病毒药物的管道。CAMPP的具体重点将 开发抗冠状病毒SARS-CoV-2（SCV 2），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，包括埃博拉丝状病毒和布尼亚病毒 严重发热伴血小板减少综合征病毒和拉沙病毒。感染这些病原体的任何一种都有 可能导致严重的人类疾病，具有显著的死亡率和目前的抗病毒药物选择 治疗是有限的。抗病毒药物瑞德西韦和几种单克隆抗体治疗已经收到 紧急使用授权（EUA）用于治疗COVID-19，聚合酶抑制剂莫努匹拉韦， 默克有望在不久的将来获得EUA。单克隆抗体也可用于治疗埃博拉病毒 然而，由于病毒感染，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获批治疗方法。 为此，我们组建了一个世界级的多学科调查团队， 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 类器官/动物模型，他将与药物发现部门的药物开发专家密切合作， 斯克里普斯研究所，校准，以进一步发展四大类有前途的资产 在我们的药物研发流程中首先，我们建议开发一种潜在的最佳的，口服生物利用度 冠状病毒蛋白酶（CLpro）抑制剂的冠状病毒，包括SCV 2，从一个后期阶段的药物资产， ADME优化，预计将在未来三年内进入IND使能研究。二是 鉴定和优化SCV 2和其他CAMPP病毒的RNA聚合酶抑制剂，目标是达到 在今后四年内开展国家自主研发能力研究。我们建议的第三个重点是开发抗病毒药物， SCV 2编码的其他“可药物化”蛋白质和其他病毒构成大流行威胁;这些资产 包括SCV 2解旋酶、E蛋白编码离子通道活性、进入和融合活性的抑制剂， 核衣壳，目标是获得这些中期资产的子集的体内概念验证。最后， 我们建议靶向传统上被认为是“不可用药的”非酶蛋白，包括SCV 2和黄病毒 结构蛋白以及RNA结构，以开发抗病毒药物开发的新策略。CAMPP 提供了一个高度集成的基础设施的研究人员，专业知识和外部制药和创始 合作伙伴，这将确保中心的成功，实现我们的目标和导航的药物的挑战 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.