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是一场全球卫生危机，必须由政府全力应对