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:10457971
- 负责人:
- 金额:$ 72.3万
- 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 2023-07-31
- 项目状态:已结题
- 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 vivoinhibitormonolayernovelpathogenic viruspeptide Bpeptide Ipeptide analogpeptide drugpreventprophylacticprotein aminoacid sequenceprototypereceptorreceptor bindingresistance mechanismuptakeviral entry inhibitorviral transmission
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。一个简单的预防性抗病毒策略
保护天真的人免受感染。在未来,当疫苗应该可用时,
抗病毒药物对于没有产生适当免疫应答的个体是必不可少的。抗病毒药物,
病毒进入宿主细胞已被证明对广泛的病毒性疾病有效。融合/Fusion
CoV(包括SARS-CoV-2)的形成过程是由病毒包膜糖蛋白(S)介导的。一致行动
受体结合结构域和融合结构域是融合所必需的。在病毒附着(和摄取)后,
在某些情况下),大规模的构象重排发生在融合结构域中,
一种将蛋白质重折叠直接与膜融合结合的结构。这种结构的形成可以
被融合抑制肽(C-末端七肽重复或HRC肽)靶向,
S.我们已经发现,脂质与抑制剂的缀合
肽将肽引导至细胞膜并增加抗病毒功效。类似脂肽可预防
感染的几种病毒(麻疹,尼帕,副流感,流感),并可以通过管理
气道。治疗是有效的,其中一些甚至在感染后几天。此外,我们还表明,
通过用β-氨基酸残基周期性替换α-氨基酸残基来修饰HRC肽的骨架,
氨基酸残基产生α/β-肽,其保留抗病毒效力(针对HIV或副流感病毒),
对蛋白水解有很强的抵抗力。我们最近合成了一种HRC脂肽,它对SARS和
CoV 2和MERS活病毒在体外,阻断SARS-CoV 2在人气道组织中的传播,
在直接接触的雪貂之间传播SARS-CoV-2。在此,我们建议将脂质联合收割机
缀合和骨架修饰策略,以产生有效的SARS-CoV 2感染抑制剂,
在体内显示出很长的半衰期。
1.优化SARS-CoV-2 HRC肽融合抑制剂的抗病毒效力和生物利用度
理性分子工程α/β-脂肽候选物的抗病毒功效将在
在真实病毒感染和人气道模型中进行定量体外测定。
2.评价新型骨架修饰的α/β-脂肽融合抑制剂对以下疾病的保护作用:
SARS-CoV-2感染仓鼠。骨架修饰的S-25的体内生物分布和毒性分析
CoV-2 α/β-脂肽融合抑制剂和体内效力和耐药机制的评估将奠定
为安全有效的SARS CoV-2融合抑制剂预防冠状病毒奠定了基础,
疗法
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:
$ 72.3万 - 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:
$ 72.3万 - 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:
10237621 - 财政年份:2021
- 资助金额:
$ 72.3万 - 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:
$ 72.3万 - 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:
$ 72.3万 - 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:
$ 72.3万 - 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:
$ 72.3万 - 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:
$ 72.3万 - 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:
$ 72.3万 - 项目类别:
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