权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
10359085
负责人：
Joseph Stone Doggett
金额：
--
依托单位：
PORTLAND VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2023-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10359085
关键词：
2019-nCoV 4-aminoquinoline Age Animal Model Animals Antiviral Agents Biological Assay COVID-19 COVID-19 impact 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-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 coronavirus 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

项目摘要

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.

新冠肺炎是一场全球性的健康危机，必须以政府的全部能力加以应对各机构、私营部门和科学界。广泛有效的新药冠状病毒是结束这一大流行和预防未来冠状病毒大流行的关键工具。由于年龄较大和心血管疾病的发生率较高，退伍军人患严重新冠肺炎的风险尤其高疾病。重新调整新冠肺炎药物用途的初步努力，重新唤起了人们对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发现了许多致病病毒，但这些结果并未转化为临床益处。中国的初步临床观察提示，羟氯喹可能会改善临床结果，但AS 然而，这一证据仍然没有定论。总体而言，氯喹广泛的抗病毒活性表明应通过评估靶向机制相似的化合物来优化抗病毒机制在病毒致病过程中必不可少的细胞内内体。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。在机制上类似于羟基氯喹对SARS-CoV-2和相关的人类冠状病毒的作用。这些化合物的心脏毒性比氯喹小，并能增强体内的蓄积。疟原虫消化液泡；通过产生更高的病毒进入宿主细胞所需的细胞内体中的药物浓度。初步抗病毒检测将识别用于临床前评估和优先排序的HITS，并提供广泛的结构-活动- 指导合成具有更大抗病毒效力的新化合物的关系。最有效的化合物对人体细胞没有毒性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。来自这些研究的早期先导化合物将迅速推进到在动物模型中的测试 SARS-CoV-2、其他致病冠状病毒和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最初的抗病毒测试、人体细胞毒性研究和靶标识别以确定结构特征增强抗病毒活性的药物。基于这些模型，新的抗病毒药物4-氨基喹啉将被创造出来，并以与抗病毒筛查中的命中化合物相同的方式进行评估。这项研究将建立在改变用途的化合物羟氯喹，以快速识别以更大剂量的抗病毒药物为靶标的内体冠状病毒的临床疗效和安全性。