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
基本信息
- 批准号:10221150
- 负责人:
- 金额:$ 44.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:2019-nCoVAffinityAmino AcidsAntiviral AgentsApplications GrantsBacteriophagesBindingBiological AssayBiophysicsCaringCellsCellular MembraneCellular biologyCessation of lifeChemicalsCholesterolClinical ResearchCollaborationsComplexCoronavirusCoronavirus spike proteinDoseDrug ScreeningDrug TargetingEbolaElementsEnvironmentFamilyFluorescence PolarizationFutureGoalsHIVHIV-1Half-LifeHumanImageInfectionInfection preventionInstitutesLeadLibrariesLigationLuciferasesMeasuresMembraneMembrane FusionMiddle East Respiratory Syndrome CoronavirusModificationPeptide HydrolasesPeptide SynthesisPeptidesPhage DisplayPhasePreventive treatmentProcessProductionProteinsResearchResolutionRespiratory SystemSARS coronavirusSevere Acute Respiratory SyndromeSolidStructureSurface Plasmon ResonanceTechnologyTestingTherapeuticTherapeutic IndexUniversitiesUtahVaccinesVesicular stomatitis Indiana virusViralVirusWorkX-Ray Crystallographybasecombatcytotoxicitydesigndrug discoveryeconomic impacthuman coronavirusimmunogenicityimprovedinhibitor/antagonistinnovationnovelnovel coronaviruspandemic diseaseprotein aminoacid sequencescaffoldscreeningstructural biologytooltraffickingvirus envelope
项目摘要
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Michael S Kay其他文献
Michael S Kay的其他文献
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{{ truncateString('Michael S Kay', 18)}}的其他基金
University of Utah Medical Scientist Training Program
犹他大学医学科学家培训计划
- 批准号:
10628815 - 财政年份:2023
- 资助金额:
$ 44.94万 - 项目类别:
CHEETAH Center for the Structural Biology of HIV Infection, Restriction, and Viral Dynamics
CHEETAH HIV 感染、限制和病毒动力学结构生物学中心
- 批准号:
10508314 - 财政年份:2022
- 资助金额:
$ 44.94万 - 项目类别:
CHEETAH Center for the Structural Biology of HIV Infection, Restriction, and Viral Dynamics
CHEETAH HIV 感染、限制和病毒动力学结构生物学中心
- 批准号:
10663353 - 财政年份:2022
- 资助金额:
$ 44.94万 - 项目类别:
Targeting SARS-Related Coronaviruses with a D-peptide Entry Inhibitor
使用 D 肽进入抑制剂靶向 SARS 相关冠状病毒
- 批准号:
10189371 - 财政年份:2020
- 资助金额:
$ 44.94万 - 项目类别:
Program for Interdisciplinary Training in CHemical Biology
化学生物学跨学科培训计划
- 批准号:
10418768 - 财政年份:2018
- 资助金额:
$ 44.94万 - 项目类别:
Program for Interdisciplinary Training in CHemical Biology
化学生物学跨学科培训计划
- 批准号:
10179423 - 财政年份:2018
- 资助金额:
$ 44.94万 - 项目类别:
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