Engineering protease-resistant antiviral peptide inhibitors for SARS-CoV-2
设计针对 SARS-CoV-2 的蛋白酶抗性抗病毒肽抑制剂
基本信息
- 批准号:10237621
- 负责人:
- 金额:$ 77.34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:2019-nCoVAmino AcidsAnimalsAntiviral AgentsAntiviral resistanceBindingBiodistributionBiological AssayBiological AvailabilityBiophysicsC-terminalCOVID-19 pandemicCOVID-19 treatmentCell Culture TechniquesCell fusionCell membraneCell surfaceCellsCholesterolClinicalCoronavirusCoronavirus InfectionsCouplesDataDiseaseDisease OutbreaksDoseEngineeringEvolutionFerretsFoundationsFutureGenerationsGlycoproteinsGoalsHIVHalf-LifeHamstersHumanImmune responseIndividualInfectionInfection preventionInfluenzaIntegration Host FactorsLipidsMeaslesMeasuresMediatingMembraneMembrane FusionMiddle East Respiratory SyndromeMiddle East Respiratory Syndrome CoronavirusModelingModificationMolecularMolecular ConformationParainfluenzaParamyxovirusPeptide HydrolasesPeptidesPerformancePeriodicityPlayPredispositionPrevention therapyProcessProphylactic treatmentProtein EngineeringProteinsProteolysisRegimenResistanceRoleSARS coronavirusSARS-CoV-2 antiviralSARS-CoV-2 entry inhibitorSARS-CoV-2 infectionSARS-CoV-2 inhibitorSARS-CoV-2 spike proteinSARS-CoV-2 transmissionSiteStructureTherapeuticTissuesToxic effectTranslatingVaccinesVertebral columnViralVirusVirus DiseasesVirus-Cell Membrane InteractionWorkairway epitheliumanti-viral efficacybasebetacoronavirusclinical efficacycomparative efficacycoronavirus treatmentdesignexperimental studyimprovedin vivoinhibitor/antagonistmonolayernovelpathogenic viruspeptide Bpeptide Ipeptide analogpeptide drugpreventprophylacticprotein aminoacid sequenceprototypereceptorreceptor bindingresistance mechanismuptakeviral entry inhibitorviral transmissionvirology
项目摘要
No vaccines or treatments for SARS-CoV-2 are yet available. A simple prophylactic antiviral strategy would
protect naïve individuals from infection now. In the future, when vaccines should be available, a prophylactic
antiviral will be essential for individuals who do not mount a suitable immune response. Antivirals that target
viral entry into the host cell have been proven effective against a wide range of viral diseases. The entry/fusion
process for CoV (including SARS-CoV-2) is mediated by the viral envelope glycoprotein (S). Concerted action
by the receptor-binding domain and the fusion domain is required for fusion. Upon viral attachment (and uptake
in certain cases), large-scale conformational rearrangements occur in the fusion domain, driven by formation of
a structure that couples protein refolding directly to membrane fusion. The formation of this structure can be
targeted by fusion inhibitory peptides (C-terminal heptad repeat or HRC peptides) that prevent proper
apposition of the HRC and HRN domains in S. We have found that conjugation of a lipid to an inhibitory
peptide directs the peptide to cell membranes and increases antiviral efficacy. Analogous lipo-peptides prevent
infection by several viruses (measles, Nipah, parainfluenza, influenza), and can be administered via the
airway. Treatment is effective for some of these even several days after infection. In addition, we have shown
that modifying the backbone of an HRC peptide via periodic replacement of α-amino acid residues with β-
amino acid residues generates α/β-peptides that retain antiviral potency (toward HIV or parainfluenza) but are
highly resistant to proteolysis. We recently generated an HRC lipopeptide that is effective against both SARS-
CoV2 and MERS live viruses in vitro, blocks spread of SARS-CoV2 in human airway tissue, and inhibits
transmission of SARS-CoV-2 between ferrets in direct contact. Here we propose to combine the lipid
conjugation and backbone-modification strategies to generate potent inhibitors of SARS-CoV2 infection that
display a long half-life in vivo.
1. Optimize the antiviral potency and bioavailability of SARS-CoV-2 HRC peptide fusion inhibitors via
rational molecular engineering. Antiviral efficacy of α/β-lipopeptide candidates will be measured in
quantitative in vitro assays, in authentic virus infection, and in a human airway model.
2. Evaluate the protection afforded by new backbone-modified α/β-lipopeptide fusion inhibitors against
SARS-CoV-2 infection in hamsters. Analysis of in vivo biodistribution and toxicity of backbone modified S-
CoV-2 α/β-lipopeptide fusion inhibitors and assessment of in vivo potency and resistance mechanisms will lay
the foundation for a safe and effective SARS CoV-2 fusion inhibitor for coronavirus prevention and
therapy.
目前还没有针对SARS-CoV-2的疫苗或治疗方法。一种简单的预防性抗病毒策略将
现在就保护天真的人不受感染。在未来,当疫苗应该可用时,一种预防性的
对于没有产生适当免疫反应的个人来说,抗病毒药物将是必不可少的。靶向抗病毒药物
病毒进入宿主细胞已被证明对多种病毒疾病有效。进入/融合
冠状病毒(包括SARS-CoV-2)的形成过程是由病毒包膜糖蛋白(S)介导的。协调一致的行动
由受体结合域和融合域进行融合所需。基于病毒附着(和感染
在某些情况下),在融合结构域中发生大规模构象重排,驱动因素是形成
一种将蛋白质重折叠直接连接到膜融合的结构。这种结构的形成可以是
以融合抑制肽(C-末端七肽重复序列或HRC肽)为靶点,以防止适当的
S中HRC和HRN结构域的结合我们发现一种脂质与一种抑制性物质的结合
多肽将多肽导向细胞膜,增加抗病毒效果。类似脂肽预防
感染多种病毒(麻疹、尼帕、副流感、流感),可通过
气道口。即使在感染几天后,治疗对其中一些也是有效的。此外,我们还展示了
通过周期性地将α-氨基酸残基替换为β-氨基酸残基来修饰HRC肽的骨架。
氨基酸残基产生α/β-肽,保持抗病毒效力(针对艾滋病毒或副流感),但
高度耐蛋白质水解性。我们最近产生了一种HRC脂肽,它对两种SARS都有效-
CoV2和MERS体外活病毒,阻断SARS-CoV2在人呼吸道组织中的传播,并抑制
SARS-CoV-2在直接接触的雪貂之间的传播。在这里,我们建议将脂类
接合和骨架修饰策略以产生有效的SARS-CoV2感染抑制剂,
在体内显示出很长的半衰期。
1.通过优化SARS-CoV-2 HRC多肽融合抑制剂的抗病毒效力和生物利用度
合理的分子工程。α/β-脂肽候选的抗病毒效果将在
在真实的病毒感染和人类呼吸道模型中进行体外定量分析。
2.评价新型骨架修饰的α/β-脂肽融合抑制剂对机体的保护作用
仓鼠感染SARS-CoV-2。骨架修饰S-的体内生物分布及毒性分析
冠状病毒-2α/β-脂肽融合抑制剂及其体内效力和耐药机制的评估
用于冠状病毒预防和控制的安全有效的SARS CoV-2融合抑制剂的基础
心理治疗。
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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Anne Moscona其他文献
Anne Moscona的其他文献
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{{ truncateString('Anne Moscona', 18)}}的其他基金
Broad spectrum inhibitors of paramyxovirus envelope proteins
副粘病毒包膜蛋白的广谱抑制剂
- 批准号:
10634368 - 财政年份:2023
- 资助金额:
$ 77.34万 - 项目类别:
Engineering protease-resistant antiviral peptide inhibitors for SARS-CoV-2
设计针对 SARS-CoV-2 的蛋白酶抗性抗病毒肽抑制剂
- 批准号:
10457971 - 财政年份:2021
- 资助金额:
$ 77.34万 - 项目类别:
Engineering protease-resistant antiviral peptide inhibitors for SARS-CoV-2
设计针对 SARS-CoV-2 的蛋白酶抗性抗病毒肽抑制剂
- 批准号:
10669579 - 财政年份:2021
- 资助金额:
$ 77.34万 - 项目类别:
Design of CNS-targeted peptide entry inhibitors for emerging henipaviruses
针对新兴亨尼帕病毒的中枢神经系统靶向肽进入抑制剂的设计
- 批准号:
9251618 - 财政年份:2016
- 资助金额:
$ 77.34万 - 项目类别:
Design of CNS-targeted peptide entry inhibitors for emerging henipaviruses
针对新兴亨尼帕病毒的中枢神经系统靶向肽进入抑制剂的设计
- 批准号:
8868022 - 财政年份:2012
- 资助金额:
$ 77.34万 - 项目类别:
Design of CNS-targeted peptide entry inhibitors for emerging henipaviruses
针对新兴亨尼帕病毒的中枢神经系统靶向肽进入抑制剂的设计
- 批准号:
8366672 - 财政年份:2012
- 资助金额:
$ 77.34万 - 项目类别:
Design of CNS-targeted peptide entry inhibitors for emerging henipaviruses
针对新兴亨尼帕病毒的中枢神经系统靶向肽进入抑制剂的设计
- 批准号:
8841461 - 财政年份:2012
- 资助金额:
$ 77.34万 - 项目类别:
Design of CNS-targeted peptide entry inhibitors for emerging henipaviruses
针对新兴亨尼帕病毒的中枢神经系统靶向肽进入抑制剂的设计
- 批准号:
8486390 - 财政年份:2012
- 资助金额:
$ 77.34万 - 项目类别:
A novel antiviral platform: untimely activation of viral fusion mechanisms will
新型抗病毒平台:病毒融合机制的不及时激活将
- 批准号:
8302529 - 财政年份:2011
- 资助金额:
$ 77.34万 - 项目类别:
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