COVID19: Optimized Endosome-Targeting Compounds for SARS-CoV-2 and Emerging Coronaviruses

COVID-19是一场全球性的健康危机，必须以政府的全部能力来应对 机构、私营部门和科学界。广泛有效的新药， 冠状病毒是结束这场大流行和预防未来冠状病毒大流行的重要工具。 退伍军人由于年龄较大和心血管疾病发生率较高， 疾病重新利用药物治疗COVID-19的初步努力重新引起了人们对4-羟色胺抗病毒活性的兴趣。 氨基喹啉类：氯喹和羟氯喹。氯喹已显示出作为抗病毒药物的前景， 在过去的临床前研究中，许多致病性病毒，但这些结果并没有转化为临床效益。 在中国的初步临床观察表明，羟氯喹可能改善临床结局，但作为一种治疗方法， 然而，这一证据仍然是不确定的。总的来说，氯喹广泛的抗病毒活性表明， 抗病毒机制，应通过评估机制相似的化合物，靶向优化 细胞内核内体是病毒致病所必需的。 这项研究计划将测试4-氨基喹啉和氨基吖啶酮的重点化学库 其机制类似于羟氯喹抗SARS-CoV-2和相关人类冠状病毒。 这些化合物被设计成具有比氯喹更少的心脏毒性，并且增强了在体内的积累。 疟原虫消化泡;通过产生更高的抗病毒效果， 病毒进入宿主细胞所需的细胞内体中的药物浓度。初始抗病毒检测 将识别用于临床前评价和优先级排序的命中，并提供广泛的结构-活性- 关系，以指导合成具有更大抗病毒效力的新化合物。最有效的化合物 对人体细胞无毒的药物将进行靶点特异性、心脏毒性和药代动力学测试。 可行性从这些研究中获得的早期先导化合物将很快在动物模型中进行测试， SARS-CoV-2，其他致病性冠状病毒和通过单独资助的进一步临床前测试 机制对于构效关系，计算药效团建模将使用结果 初步的抗病毒测试，人体细胞毒性研究和目标识别，以确定结构特征 增强抗病毒活性。基于这些模型，将产生新的抗病毒4-氨基喹啉， 以与来自抗病毒筛选的命中化合物相同的方式评价。这项研究将建立在 重新利用的化合物羟氯喹，以快速识别具有更大 冠状病毒的临床有效性和安全性。

COVID-19 is a global health crisis that must be countered with the full capacity of government agencies, the private sector and the scientific community. New drugs that are broadly effective against coronaviruses are a crucial tool for ending this pandemic and preventing future coronavirus pandemics. Veterans are particularly at risk for severe COVID-19 due to older age and higher rates of cardiovascular disease. Initial efforts to repurpose drugs for COVID-19 have revived interest in the antiviral activity of the 4- aminoquinolines: chloroquine and hydroxychloroquine. Chloroquine has shown promise as an antiviral against many pathogenic viruses in past preclinical studies, but these results have not translated into clinical benefit. Initial clinical observations in China suggested that hydroxychloroquine may improve clinical outcomes, but as of yet, this evidence remains inconclusive. Overall, chloroquine’s broad antiviral activity indicates a promising antiviral mechanism that should be optimized by evaluating mechanistically similar compounds that target intracellular endosomes that are essential for viral pathogenesis. This research proposal will test a focused chemical library of 4-aminoquinolines and aminoacridones that are mechanistically similar to hydroxychloroquine against SARS-CoV-2 and related human coronaviruses. These compounds were designed to have less cardiac toxicity than chloroquine and enhanced accumulation in the Plasmodium digestive vacuole; properties that will likely lead to greater antiviral efficacy by creating higher drug concentrations in the intracellular endosomes that viruses require for host cell entry. Initial antiviral testing will both identify hits for preclinical evaluation and prioritization, and provide an extensive structure-activity- relationship to guide synthesis of new compounds with greater antiviral potency. The most potent compounds that are not toxic to human cells will be tested for target specificity, cardiac toxicity, and pharmacokinetic feasibility. The early lead compounds from these studies will be rapidly advanced to testing in animal models of SARS-CoV-2, other pathogenic coronaviruses and further preclinical testing via a separate funding mechanism. For the structure-activity-relationship, computational pharmacophore modeling will use the results of the initial antiviral testing, human cytotoxicity studies and target identification to identify structural features that enhance antiviral activity. Based on these models, new antiviral 4-aminoquinolines will be created and evaluated in the same manner as the hit compounds from the antiviral screen. This research will build on the repurposed compound, hydroxychloroquine, to quickly identify endosome targeting antivirals with greater clinical efficacy and safety for coronaviruses.