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，必须与政府的全部能力相抵抗 机构，私营部门和科学界。广泛有效地反对的新药 冠状病毒是结束这一大流行并防止未来冠状病毒大流行病的关键工具。 由于年龄较大和心血管较高的率，退伍军人特别有严重的共同造成重视的风险 疾病。重新利用药物的最初努力为COVID-19恢复了对4--的抗病毒活性的兴趣 氨基喹啉：氯喹和羟基氯喹。氯喹已表现出有望作为抗病毒 在过去的临床前研究中，许多致病性病毒尚未转化为临床益处。 中国最初的临床观察结果表明，羟氯喹可以改善临床结果，但AS AS 关于这些证据仍然尚无定论。总体而言，氯喹的广泛抗病毒活性表明有望 应通过评估靶向的机械相似化合物来优化的抗病毒机制 对病毒发病机理必不可少的细胞内内体。 该研究建议将测试一个重点的4-氨基喹啉和氨基酸酮的化学库 机械上类似于针对SARS-COV-2和相关人冠状病毒的羟氯喹。 这些化合物被设计为比氯喹的心脏毒性较少，并且在 疟原虫消化效果；通过创造更高的抗病毒效率可能会提高抗病毒效率的特性 病毒需要进入宿主细胞的细胞内内体中的药物浓度。初始抗病毒测试 都将确定用于临床前评估和优先次序的命中，并提供广泛的结构活性 - 指导具有更大抗病毒效力的新化合物的合成的关系。最有效的化合物 对人类细胞无毒的目标特异性，心脏毒性和药代动力学的毒性将测试 可行性。这些研究的早期铅化合物将在动物模型中迅速发展为测试 SARS-COV-2，其他致病性冠状病毒和通过单独资金进行进一步的临床前测试 机制。对于结构激活关系，计算药效团建模将使用结果 最初的抗病毒测试，人类细胞毒性研究和靶标识别以识别结构特征 这增强了抗病毒活性。基于这些模型，将创建新的抗病毒4-氨基喹啉，并 以与抗病毒筛查的HIT化合物相同的方式进行评估。这项研究将基于 重新利用的化合物羟氯喹，以快速鉴定靶向抗病毒药的内体 冠状病毒的临床效率和安全性。