design and rapid production of a drug-screening target from the highly conserved HR1 region of the viral spike protein (S2)

从病毒刺突蛋白 (S2) 高度保守的 HR1 区域设计并快速生产药物筛选靶点

• 批准号: 10221150
• 负责人: Michael S Kay
• 金额: $ 44.94万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10221150
• 关键词: 2019-nCoV; Affinity; Amino Acids; Antiviral Agents; Applications Grants; Bacteriophages; Binding; Biological Assay; Biophysics; Caring; Cells; Cellular Membrane; Cellular biology; Cessation of life; Chemicals; Cholesterol; Clinical Research; Collaborations; Complex; Coronavirus; Coronavirus spike protein; Dose; Drug Screening; Drug Targeting; Ebola; Elements; Environment; Family; Fluorescence Polarization; Future; Goals; HIV; HIV-1; Half-Life; Human; Image; Infection; Infection prevention; Institutes; Lead; Libraries; Ligation; Luciferases; Measures; Membrane; Membrane Fusion; Middle East Respiratory Syndrome Coronavirus; Modification; Peptide Hydrolases; Peptide Synthesis; Peptides; Phage Display; Phase; Preventive treatment; Process; Production; Proteins; Research; Resolution; Respiratory System; SARS coronavirus; Severe Acute Respiratory Syndrome; Solid; Structure; Surface Plasmon Resonance; Technology; Testing; Therapeutic; Therapeutic Index; Universities; Utah; Vaccines; Vesicular stomatitis Indiana virus; Viral; Virus; Work; X-Ray Crystallography; base; combat; cytotoxicity; design; drug discovery; economic impact; human coronavirus; immunogenicity; improved; inhibitor/antagonist; innovation; novel; novel coronavirus; pandemic disease; protein aminoacid sequence; scaffold; screening; structural biology; tool; trafficking; virus envelope

SARS-CoV-2, a novel coronavirus, is the causative agent of the current worldwide pandemic that has already led to over 2 million infections, 125,000 deaths, and severe economic impact. Currently no preventatives, treatments, or vaccines are available, and care is solely supportive. Additionally, the 21st century has seen the emergence of multiple lethal human coronaviruses (SARS-CoV, MERS-CoV, and now SARS- CoV-2). There is an urgent need for new options to combat this and inevitable future pandemics. Coronaviruses infect cells using a conserved entry mechanism shared by enveloped viruses across multiple families in which two regions of the trimeric viral spike protein (HR1 and HR2) form a highly stable 6- helix bundle structure, juxtaposing the viral and cellular membranes to induce membrane fusion. Inhibiting formation of this 6-helix bundle stops viral entry and prevents infection. Our lab specializes in an innovative enantiomeric screening technology (mirror-image phage display) in concert with structure-guided design, to produce novel, synthetic, D-peptide viral entry inhibitors, including CPT31, our highly potent, broadly active HIV-1 D-peptide inhibitor that has been cleared by the FDA for clinical studies. Research by us and others on SARS, a highly related coronavirus that shares 86% identity (and 95% similarity) to SARS-CoV-2 in the spike HR1, indicate that these inhibition strategies should successfully block the current coronavirus. D-peptides (peptides composed of mirror-image D-amino acids) cannot be digested by proteases in the body and, therefore, possess significant therapeutic advantages including extended half-life, lower dosing, reduced immunogenicity (not digested for MHC presentation), and durability in protease-rich environments such as the respiratory tract. In this one-year grant application, we will first design and synthesize SARS-CoV-2 trimeric HR1-based peptides. These peptides accurately mimic HR1 as it appears on the virus during entry and are therefore invaluable drug screening targets. We will then use these mimics as targets in mirror-image phage display to identify D-peptide inhibitors of SARS-CoV-2 that block it and future SARS-related coronaviruses.

SARS-CoV-2是一种新型冠状病毒，是当前全球大流行的病原体，已导致200多万人感染，12.5万人死亡，并造成严重的经济影响。目前没有预防、治疗或疫苗可用，护理完全是支持性的。此外，21世纪出现了多种致命的人类冠状病毒（SARS- cov、MERS-CoV和现在的SARS- CoV-2）。迫切需要新的选择办法来对付这一流行病和未来不可避免的流行病。