Structure-guided design of protease-resistant, lipopeptide inhibitors of SARS-CoV-2
SARS-CoV-2 蛋白酶抗性脂肽抑制剂的结构指导设计
基本信息
- 批准号:10679139
- 负责人:
- 金额:$ 6.87万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-03-01 至 2026-02-28
- 项目状态:未结题
- 来源:
- 关键词:2019-nCoVAddressAmino Acid SubstitutionAmino AcidsAnimal ModelAntiviral AgentsBiodistributionBiological AssayBiological AvailabilityC-terminalCOVID-19COVID-19 therapeuticsCell membraneCellsCessation of lifeChemicalsCholesterolCircular DichroismCollaborationsCoronavirusCrystallizationCrystallographyDataDevelopmentDoseDrug KineticsEconomicsEngineeringEtiologyExhibitsFluorescence PolarizationFoundationsGoalsHIVHalf-LifeHybridsIn VitroInfectionLearningLengthMediatingMembrane FusionMembrane ProteinsMiddle East Respiratory SyndromeModificationMolecularMolecular ConformationN-terminalPara-Influenza Virus Type 3PathogenesisPeptide HydrolasesPeptidesPositioning AttributePredispositionProductivityPropertyProphylactic treatmentProtein EngineeringProteinsProteolysisResearchResearch PersonnelResistanceResolutionSARS coronavirusSARS-CoV-2 infectionSARS-CoV-2 inhibitorSARS-CoV-2 variantSideSiteStructureSurfaceTechniquesTherapeutic AgentsTreatment EfficacyUniversitiesVaccinesVariantVertebral columnViralViral PhysiologyVirusVirus DiseasesVirus InhibitorsVulnerable PopulationsWisconsinWorkX ray diffraction analysisX-Ray Crystallographyanalogcareercoronavirus diseasedesignexperienceimprovedin vivoinhibitorinsightinterdisciplinary approachmimicrynovelnovel strategiesnovel therapeuticspandemic diseaseprotein expressionviral entry inhibitorvirology
项目摘要
PROJECT SUMMARY
Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the etiological agent of coronavirus
disease (COVID-19), has spurred an unprecedented global pandemic. Infection surges necessitate new
therapeutic agents that are effective against a rapidly changing virus. Antivirals that inhibit viral entry into host
cells have proven effective against other viruses with similar mechanisms of pathogenesis.
The long-term objective of this highly collaborative proposed research is to develop potent peptides
inhibitors of SARS-CoV-2 infection that operate by blocking structural rearrangements of the spike protein
required for viral entry into host cells. For SARS-CoV-2 infection to occur, the viral surface spike (S) protein, a
homotrimer, rearranges to form an energetically favored postfusion state. In this postfusion conformation, two
helical domains, the N-terminal (HRN) and C-terminal (HRC) heptad repeats, associate to form a 6-helix bundle
(6HB). Peptides derived from the HRC can inhibit formation of the 6HB, and thus SARS-CoV-2 infection.
However, conventional peptides, composed entirely of α-amino acid residues, are highly susceptible to
proteolytic degradation, which necessitates frequent and high dosing. The Gellman lab, in collaboration with
virologists Prof. Anne Moscona and Prof. Matteo Porotto at Columbia University, has demonstrated that site-
selective incorporation of backbone modifications, in combination with cholesterol conjugation, can decrease
proteolytic sensitivity while maintaining high antiviral potency. Our team recently found that such lipopeptides
can inhibit SARS-CoV-2 infection in biological assays and animal models, and that these inhibitors are effective
against SARS-CoV-2 variants, SARS-CoV-1 and MERS. Building on this foundation, my proposed project seeks
to develop lipopeptides containing backbone modifications that display high antiviral potency and resist
proteolysis. Aim 1 will produce potent inhibitors of SARS-CoV-2 (and other coronaviruses) that contain backbone
modifications and resist proteolysis. Aim 2 will evaluate the stability of 6HB formation between inhibitor
candidates and the native SARS-CoV-2 HRN. Aim 3 will elucidate critical structural interactions between the
HRC mimics and the native HRN.
My hypothesis is that site-selective incorporation of backbone modifications into HRC-based designs will
increase both antiviral activity and half-life in vivo, improving therapeutic efficacy. The proposed research, which
will be conducted under the guidance of Prof. Sam Gellman at the University of Wisconsin, will provide me with
experience in macromolecular X-ray crystallography, molecular design, protein engineering & expression, and
virology. Through structure-guided engineering and sophisticated and multi-pronged assay
implementation, these efforts could generate effective pan-variant therapeutics for COVID-19.
项目总结
严重急性呼吸综合征2型冠状病毒,冠状病毒的病原体
新冠肺炎引发了一场史无前例的全球大流行。感染激增需要新的
对快速变化的病毒有效的治疗剂。抑制病毒进入宿主的抗病毒药物
细胞已被证明对具有类似致病机制的其他病毒有效。
这项高度合作的拟议研究的长期目标是开发有效的多肽。
通过阻断S蛋白结构重排发挥作用的SARS-CoV-2感染抑制剂
病毒进入宿主细胞所必需的。为了发生SARS-CoV-2感染,病毒表面尖峰(S)蛋白,a
高三聚体,重新排列形成能量有利的融合后状态。在这个融合后的构象中,有两个
螺旋结构域,N-末端(HRN)和C-末端(HRC)七肽重复,结合形成一个6-螺旋束
(6HB)。从HRC中提取的多肽可以抑制6HB的形成,从而抑制SARS-CoV-2感染。
然而,传统的多肽,完全由α-氨基酸残基组成,对
蛋白质降解,这需要频繁和高剂量。盖尔曼实验室,与
哥伦比亚大学的病毒学家Anne Moscona教授和Matteo Porotto教授已经证明了这个站点--
选择性地加入骨架修饰,结合胆固醇结合,可以降低
蛋白分解敏感性,同时保持较高的抗病毒效力。我们的团队最近发现这种脂肽
在生物测试和动物模型中可以抑制SARS-CoV-2的感染,并且这些抑制剂是有效的
针对SARS-CoV-2变种、SARS-CoV-1和MERS。在此基础上,我提出的项目旨在
开发含有骨架修饰的具有高抗病毒效力和抵抗力的脂肽
蛋白质分解。AIM 1将生产含有骨架的SARS-CoV-2(和其他冠状病毒)的有效抑制剂
修饰和抵抗蛋白质降解。目的2将评价缓蚀剂之间6HB形成的稳定性
候选者和SARS-CoV-2的本地HRN。目标3将阐明关键的结构相互作用
HRC模仿和原生HRN。
我的假设是,在基于HRC的设计中选择性地将主干修改合并到一起将
提高体内抗病毒活性和半衰期,提高治疗效果。拟议的研究,即
将在威斯康星大学萨姆·盖尔曼教授的指导下进行,将为我提供
具有高分子X射线结晶学、分子设计、蛋白质工程和表达经验,以及
病毒学。通过结构导向工程和复杂多管齐下的分析
如果实施,这些努力可以为新冠肺炎带来有效的泛变异疗法。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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Ariel Jade Kuhn其他文献
Ariel Jade Kuhn的其他文献
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{{ truncateString('Ariel Jade Kuhn', 18)}}的其他基金
Elucidating the biophysical and biological properties of the p3 fragment in Alzheimer's Disease
阐明阿尔茨海默病中 p3 片段的生物物理和生物学特性
- 批准号:
10065425 - 财政年份:2019
- 资助金额:
$ 6.87万 - 项目类别:
Elucidating the biophysical and biological properties of the p3 fragment in Alzheimer's Disease
阐明阿尔茨海默病中 p3 片段的生物物理和生物学特性
- 批准号:
10228755 - 财政年份:2019
- 资助金额:
$ 6.87万 - 项目类别:
Elucidating the biophysical and biological properties of the p3 fragment in Alzheimer's Disease
阐明阿尔茨海默病中 p3 片段的生物物理和生物学特性
- 批准号:
9910051 - 财政年份:2019
- 资助金额:
$ 6.87万 - 项目类别:
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