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

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（CoV）可引起危及生命的疾病，这是最近出现的与冠状病毒相关的疾病。 世界卫生组织将其命名为 2019 冠状病毒病（简称“COVID-19”）。 与它的前身 SARS-CoV 和 MERS-CoV 一样，SARS-CoV-2 (S-CoV-2) 是由 SARS-CoV-2 引起的。 β冠状病毒最初被认为起源于蝙蝠，但它的传播是从动物到人类。 目前尚无针对 COVID-19 的疫苗和治疗方法， 迫切需要这些药物来应对疫情以及不可避免的持续感染。 靶向病毒进入宿主细胞已被证明对多种病毒有效。 我们将把我们的基础研究成果应用到新型SARS肽抑制剂的开发中 我们设计了脂质缀合的融合抑制肽，可以有效抑制冠状病毒。 我们建议合成和评估新型脂化肽。 将评估这些抑制剂针对活 SARS-CoV-2 病毒的抗病毒活性。 有前途的候选者将在雪貂模型中进行传输实验测试。 确定我们抑制 SARS-CoV-2 进入的方法是否可以预防体内感染。 1. 优化HRC-脂肽融合抑制剂的抗病毒效力。 2. 临床前评估HRC-脂肽融合抑制剂的生物分布、毒性和保护作用 对抗 SARS-CoV-2 体内感染或传播。

项目成果

Potency of Fusion-Inhibitory Lipopeptides against SARS-CoV-2 Variants of Concern.

• DOI: 10.1128/mbio.01249-22
• 发表时间: 2022-06-28
• 期刊: MBIO
• 影响因子: 6.4
• 作者: Schmitz, Katharina S.;Geers, Daryl;de Vries, Rory D.;Bovier, T. Francesca;Mykytyn, Anna Z.;Geurts van Kessel, Corine H.;Haagmans, Bart L.;Porotto, Matteo;de Swart, Rik L.;Moscona, Anne
• 通讯作者: Moscona, Anne