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)可导致危及生命的疾病。最近出现的冠状病毒相关疾病 被世界卫生组织命名为冠状病毒病2019年(简称：新冠肺炎)。新冠肺炎 是由SARS-CoV-2引起的。与其前身SARS-CoV和MERS-CoV一样，SARS-CoV-2(S-CoV-2)是一种 一种被认为起源于蝙蝠的贝塔冠状病毒。最初它的传播是动物对人类的传播，但 人与人之间的传播现在很普遍。目前还没有新冠肺炎的疫苗和治疗方法， 迫切需要这些措施来应对疫情以及不可避免的持续感染。抗病毒药物 靶向病毒进入宿主细胞已被证明对多种病毒有效。在这份提案中， 我们将把我们的基础研究成果应用于开发新型SARS多肽抑制剂-- CoV-2进入。我们设计了能有效抑制冠状病毒的脂质结合融合抑制肽。 体外感染、体外感染和体内感染。我们建议合成和评估新的脂化肽 有更强的功效。这些抑制剂将被评估对活的SARS-CoV-2病毒的抗病毒活性。 有希望的候选人将在雪貂模型的变速器实验中进行测试。此应用程序将 确定我们抑制SARS-CoV-2进入的方法是否可以防止体内感染。 1.优化HRC-脂肽融合抑制剂的抗病毒效力。 2.临床前评价HRC-脂肽融合抑制剂的生物分布、毒性及保护作用 抗SARS-CoV-2感染或体内传播。

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