Fusion inhibitors that block host-to-host transmission of SARS-CoV-2

阻止 SARS-CoV-2 宿主间传播的融合抑制剂

• 批准号: 10668973
• 负责人: Matteo Porotto
• 金额: $ 71.41万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668973
• 关键词: 2019-nCoV; Abbreviations; Address; Affinity; Animals; Antiviral Agents; Binding; Biodistribution; Biological Assay; COVID-19; COVID-19 outbreak; COVID-19 pandemic; COVID-19 treatment; Cell Culture Techniques; Cell fusion; Cell membrane; Cell surface; Cells; Chiroptera; Common Cold; Coronavirus; Coronavirus Infections; Couples; Data; Development; Disease; Disease Outbreaks; Distal; Dominant-Negative Mutation; Dose; Endosomes; Ferrets; Glycoproteins; Homes for the Aged; Hospitals; Human; Immunologics; In Vitro; Infection; Infection prevention; Integration Host Factors; Life; Lipids; Mediating; Membrane; Membrane Fusion; Middle East Respiratory Syndrome Coronavirus; Modeling; Molecular; Molecular Conformation; Names; Nose; Peptide Hydrolases; Peptides; Population; Predisposition; Process; Prophylactic treatment; Proteins; SARS coronavirus; SARS-CoV-2 entry inhibitor; SARS-CoV-2 infection; SARS-CoV-2 inhibitor; SARS-CoV-2 transmission; Severe Acute Respiratory Syndrome; Severity of illness; Surface; Testing; Therapeutic Intervention; Toxic effect; Vaccinee; Vaccines; Viral; Viral Physiology; Virus; Virus Diseases; World Health Organization; Zoonoses; betacoronavirus; cell type; community transmission; cytotoxicity; design; dimer; endosome membrane; experimental study; fundamental research; genetic information; improved; in vivo; inhibitor; monomer; novel; novel coronavirus; pandemic disease; pandemic response; pre-clinical; preclinical study; pressure; prevent; receptor; receptor binding; research clinical testing; transmission process; uptake; viral transmission; virus genetics; 2019-nCoV; Abbreviations; Address; Affinity; Animals; Antiviral Agents; Binding; Biodistribution; Biological Assay; COVID-19; COVID-19 outbreak; COVID-19 pandemic; COVID-19 treatment; Cell Culture Techniques; Cell fusion; Cell membrane; Cell surface; Cells; Chiroptera; Common Cold; Coronavirus; Coronavirus Infections; Couples; Data; Development; Disease; Disease Outbreaks; Distal; Dominant-Negative Mutation; Dose; Endosomes; Ferrets; Glycoproteins; Homes for the Aged; Hospitals; Human; Immunologics; In Vitro; Infection; Infection prevention; Integration Host Factors; Life; Lipids; Mediating; Membrane; Membrane Fusion; Middle East Respiratory Syndrome Coronavirus; Modeling; Molecular; Molecular Conformation; Names; Nose; Peptide Hydrolases; Peptides; Population; Predisposition; Process; Prophylactic treatment; Proteins; SARS coronavirus; SARS-CoV-2 entry inhibitor; SARS-CoV-2 infection; SARS-CoV-2 inhibitor; SARS-CoV-2 transmission; Severe Acute Respiratory Syndrome; Severity of illness; Surface; Testing; Therapeutic Intervention; Toxic effect; Vaccinee; Vaccines; Viral; Viral Physiology; Virus; Virus Diseases; World Health Organization; Zoonoses; betacoronavirus; cell type; community transmission; cytotoxicity; design; dimer; endosome membrane; experimental study; fundamental research; genetic information; improved; in vivo; inhibitor; monomer; novel; novel coronavirus; pandemic disease; pandemic response; pre-clinical; preclinical study; pressure; prevent; receptor; receptor binding; research clinical testing; transmission process; uptake; viral transmission; virus genetics

Coronaviruses (CoVs) can cause life-threatening diseases. The recently emerging coronavirus-related illness was named coronavirus disease 2019 (abbreviated “COVID-19”) by the World Health Organization. COVID-19 is caused by SARS-CoV-2. Like its predecessors SARS-CoV and MERS-CoV, SARS-CoV-2 (S-CoV-2) is a betacoronavirus that is thought to have originated in bats. Originally its spread was animal-to-human, but human-to-human transmission is now widespread. No vaccines and treatments for COVID-19 are available, and these are urgently needed to address the outbreak as well as inevitable ongoing infection. Antivirals that target viral entry into the host cell have been proven effective against a wide range of viruses. In this proposal, we will apply the results of our fundamental research to the development of novel peptide inhibitors of SARS- CoV-2 entry. We have designed lipid-conjugated fusion-inhibitory peptides that efficiently inhibit coronavirus infection in in vitro, ex vivo, and in vivo. We propose to synthesize and evaluate novel lipidated peptides that have enhanced efficacy. These inhibitors will be evaluated for antiviral activity against live SARS-CoV-2 virus. Promising candidates will be tested in transmission experiments in a ferret model. This application will determine whether our approach to entry inhibition of SARS-CoV-2 prevents infection in vivo. 1. To optimize antiviral potency of HRC-lipopeptide fusion inhibitors. 2. To pre-clinically evaluate HRC-lipopeptide fusion inhibitors biodistribution, toxicity and protection against SARS-CoV-2 infection or transmission in vivo.

冠状病毒（COVS）可能导致威胁生命的疾病。最近新兴冠状病毒有关的疾病 被世界卫生组织称为2019年冠状病毒疾病（缩写为“ Covid-19”）。新冠肺炎 是由SARS-COV-2引起的。就像其前任SARS-COV和MERS-COV一样，SARS-COV-2（S-COV-2）也是 被认为是在蝙蝠中原创的Betacoronavirus。最初的传播是动物到人类的，但 人类到人类的传播现在已广泛。没有疫苗和Covid-19的疫苗和治疗方法， 这些迫切需要解决这些爆发以及不可避免的持续感染。抗病毒药 靶病毒进入宿主细胞已被证明有效地针对广泛的病毒有效。在此提案中， 我们将把我们的基本研究的结果应用于SARS-新型肽抑制剂的发展 COV-2条目。我们设计了脂质偶联的融合抑制辣椒，可有效抑制冠状病毒 体外感染，体内和体内感染。我们建议综合和评估新颖的脂化petides 提高效率。这些抑制剂将评估针对活体SARS-COV-2病毒的抗病毒活性。 有希望的候选人将在雪貂模型中的传输实验中进行测试。此应用程序将 确定我们对SARS-COV-2的进入方法是否阻止体内感染。 1。优化HRC-磷酸肽融合抑制剂的抗病毒效力。 2。临时评估HRC-脂肽融合抑制剂生物分布，毒性和保护 针对SARS-COV-2感染或体内传播。