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

COVID19：针对 SARS-CoV-2 和新兴冠状病毒的优化内体靶向化合物

• 批准号: 10155164
• 负责人: Joseph Stone Doggett
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10155164
• 关键词: 2019-nCoV; 4-aminoquinoline; Age; Animal Model; Animals; Antiviral Agents; Biological Assay; COVID-19; COVID-19 pandemic; COVID-19 treatment; Cardiotoxicity; Cardiovascular Diseases; Cells; China; Chiroptera; Chloroquine; Clinical; Clinical Trials; Communities; Coronavirus; Dose; Drug Kinetics; Drug Screening; Economics; Endosomes; Evaluation; Funding Mechanisms; Future; Government Agencies; Health; Health protection; Healthcare Systems; Human; Human Cell Line; Hydroxychloroquine; Image; In Vitro; Industry; Infection; Investigation; Knowledge; Lead; Life; Measures; Metabolic; Middle East Respiratory Syndrome; Modeling; Mus; Oral; Outcome; Pathogenicity; Pathway interactions; Pharmaceutical Preparations; Plasmodium; Populations at Risk; Preclinical Testing; Prevalence; Private Sector; Property; Prophylactic treatment; Public Health; Pulmonary Hypertension; Reporting; Research; Research Proposals; Risk; SARS coronavirus; SARS-CoV-2 inhibitor; SARS-CoV-2 transmission; Safety; Science; Severe Acute Respiratory Syndrome; Specificity; Structure; Structure-Activity Relationship; Survival Analysis; Symptoms; Testing; Toxic effect; United States; Vaccines; Vacuole; Vero Cells; Veterans; Viral Pathogenesis; Virus; Virus Replication; Vulnerable Populations; amphiphilicity; anti-viral efficacy; base; clinical efficacy; compound 30; cytotoxicity; design; drug repurposing; effective therapy; global health; human coronavirus; human old age (65+); improved; in vitro activity; interest; mortality; novel coronavirus; novel therapeutics; pandemic disease; pathogenic virus; pharmacophore; preclinical evaluation; preclinical study; prevent; response; severe COVID-19; small molecule libraries; tertiary amine; tool; transmission process; warfighter; zoonotic coronavirus

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.

COVID-19 是一场全球健康危机，政府必须全力应对 机构、私营部门和科学界。广泛有效的新药 冠状病毒是结束这一流行病和预防未来冠状病毒大流行的重要工具。 由于年龄较大和心血管疾病发病率较高，退伍军人尤其面临严重 COVID-19 的风险 疾病。重新利用药物治疗 COVID-19 的初步努力重新燃起了人们对 4- 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 过去的临床前研究对许多致病病毒进行了研究，但这些结果尚未转化为临床益处。 中国的初步临床观察表明，羟氯喹可能会改善临床结果，但随着 然而，这一证据仍然没有结论。总体而言，氯喹广泛的抗病毒活性表明其具有广阔的前景 应通过评估机制相似的靶向化合​​物来优化抗病毒机制 对病毒发病机制至关重要的细胞内内体。 该研究计划将测试 4-氨基喹啉和氨基吖啶酮的重点化学库 其机制与针对 SARS-CoV-2 和相关人类冠状病毒的羟氯喹相似。 这些化合物的设计目的是比氯喹具有更低的心脏毒性，并增强体内蓄积。 疟原虫消化液泡；这些特性可能会通过产生更高的抗病毒功效来产生更大的抗病毒功效 病毒进入宿主细胞所需的细胞内内体中的药物浓度。初步抗病毒测试 将确定临床前评估和优先顺序的命中，并提供广泛的结构-活性- 关系指导合成具有更强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标特异性、心脏毒性和药代动力学测试 可行性。这些研究的早期先导化合物将迅速进入动物模型测试 SARS-CoV-2、其他致病性冠状病毒以及通过单独资助进行的进一步临床前测试 机制。对于结构-活性-关系，计算药效团建模将使用结果 初始抗病毒测试、人类细胞毒性研究和目标识别以识别结构特征 增强抗病毒活性。基于这些模型，将创建新的抗病毒 4-氨基喹啉 以与抗病毒筛选中的命中化合物相同的方式进行评估。这项研究将建立在 重新利用的化合物羟氯喹，可以快速识别靶向抗病毒药物的内体 冠状病毒的临床疗效和安全性。