Small molecule-induced degradation of dengue proteins as an antiviral strategy
小分子诱导的登革热蛋白降解作为抗病毒策略
基本信息
- 批准号:10472071
- 负责人:
- 金额:$ 81.09万
- 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:2020-07-23 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AblationAffectAffinityAntiviral AgentsAntiviral resistanceBindingBiological AssayCancer BiologyCell Culture TechniquesCellsCore ProteinDengueDengue InfectionDengue VirusDevelopmentDoseDrug KineticsEventExcisionFlavivirusFoundationsGenetic VariationGenotypeGoalsHIVHepatitis CHepatitis C virusHumanIn VitroLengthLigandsLinkMediatingMembraneMethodsMonitorMutationPeptide HydrolasesPharmaceutical ChemistryPharmaceutical PreparationsPharmacologyPolymerasePredispositionProcessProteinsRNA VirusesRNA replicationRNA-Directed RNA PolymeraseResistanceResistance profileSerial PassageSerotypingSpecificitySuppressor MutationsTestingTimeUbiquitinationVaccinesViralViral GenomeViral ProteinsVirusVirus ReplicationWorkanti-viral efficacyantiviral drug developmentchemotherapycombatcytotoxicitydesignefficacy testingexperimental studyimprovedin vivoinhibitormouse modelmutantpathogenpathogenic virusprotein degradationprotein functionrecruitresidenceresistance mechanismsmall moleculetoolubiquitin-protein ligasevaccine developmentvirus core
项目摘要
PROJECT SUMMARY / ABSTRACT
Dengue virus (DENV) is a pathogen of high biomedical significance against which we lack effective
countermeasures. Although targeted chemotherapy using combinations of direct-acting antivirals (DAAs) has
proven highly successful against hepatitis C virus infection and HIV, efforts to develop analogous drugs against
DENV have not been successful. The genetic diversity of DENV due to replication by an RNA-dependent RNA
polymerase that lacks proofreading function presents additional challenges by making it difficult to develop
vaccines and antivirals with broad-spectrum coverage of all genotypes within one viral species and facilitating
the rapid development of antiviral resistance when DAAs are used as monotherapies.
Recently developed methods for small molecule-induced degradation of specific proteins rely on chimeric
molecules (“PROTACs,” “degronimids,” “degraders”) that have a target-specific ligand linked to a moiety that
binds an E3 ubiquitin ligase (e.g., cereblon, VHL). Small molecule-binding leads to ubiquitination and
proteasomal degradation of the target. This results in event-driven rather than occupancy-driven pharmacology
leading to efficient removal of the target from the cell and functional ablation of all of the protein's functions.
Since pharmacological activity does not require constant, stoichiometric engagement of the target, even modest
affinity ligands can be effective degraders. In addition, this mechanism of action can have higher natural barriers
to resistance than conventional inhibitors, as has been demonstrated in the cancer biology field. While these
potential advantages are attractive for antivirals development, it remains unclear the extent to which they can be
leveraged to attain significant antiviral effects. In particular, strong viral expression and localization of viral
processes (and their effectors) on or near specialized membranes may limit the susceptibility of DENV and other
viruses to this pharmacological strategy. Here we propose to explore whether we can successfully deploy
targeted protein degradation against three essential DENV proteins: core, NS4B, and NS5. As there are
currently no approved anti-DENV drugs, there is an urgent need to find new pharmacological strategies to target
this virus. Starting with known inhibitors as targeting ligands for degrader development, we will develop and
validate antiviral degraders. We will then use these as tools to systematically explore potential points of
differentiation between degraders and conventional inhibitors in terms of affinity, potency, selectivity, duration of
action and susceptibility to resistance. We will also optimize validated antiviral degraders to test the efficacy of
this antiviral approach in vivo. The overall goal is to validate degradation of one or more of these targets as an
antiviral strategy with high natural barrier to resistance and to advance first-in-class degraders as leads for the
development of antivirals. In pursuit of this goal, we will also establish important proof of concept and the
foundation for more broadly developing antiviral degraders against other viral pathogens.
项目摘要/摘要
登革病毒(DENV)是一种具有很高生物医学意义的病原体,但我们对其缺乏有效的治疗
对策。尽管使用直接作用抗病毒药物(DAA)组合的靶向化疗具有
事实证明,在对抗丙型肝炎病毒感染和艾滋病毒方面非常成功,努力开发类似的药物来对抗
DENV尚未成功。依赖RNA的RNA复制引起的DENV的遗传多样性
缺乏校对功能的聚合酶带来了额外的挑战,使其难以开发
疫苗和抗病毒药物,广谱覆盖一个病毒物种内的所有基因类型,并促进
当DAA作为单一疗法使用时,抗病毒耐药性迅速发展。
最近开发的小分子诱导特定蛋白质降解的方法依赖于嵌合体
分子(“PROTAC”、“DECRONIMID”、“DECHERDER”)具有目标特定的配体,连接到部分
结合E3泛素连接酶(例如,Cereblon,VHL)。小分子结合导致泛素化和
靶标的蛋白酶体降解。这导致了事件驱动而不是占用驱动的药理学
从而有效地将靶标从细胞中移除,并对蛋白质的所有功能进行功能性消融。
由于药理活性不需要持续的、化学计量比的靶标参与,即使是适度的
亲和配体可以是有效的降解剂。此外,这种作用机制可能具有更高的自然屏障。
对常规抑制剂的抗药性,已在癌症生物学领域得到证明。而这些
潜在的优势对抗病毒药物的开发是有吸引力的,但目前还不清楚它们能在多大程度上
以达到显著的抗病毒效果。尤其是强病毒表达和病毒的定位
特化膜上或其附近的过程(及其效应器)可能会限制DENV和其他
病毒对这一药理策略的影响。在这里,我们建议探索我们是否可以成功地部署
针对三种必需的DENV蛋白:CORE、NS4B和NS5的靶向蛋白质降解。就像有
目前还没有批准的抗DENV药物,迫切需要寻找新的药理策略来靶向
这种病毒。从已知的抑制剂作为降解剂开发的靶向配体开始,我们将开发和
验证抗病毒降解剂。然后,我们将使用这些工具来系统地探索潜在的
降解剂和常规抑制剂在亲和力、效力、选择性、持续时间等方面的差异
对抗性的作用和敏感性。我们还将优化经过验证的抗病毒降解剂,以测试
这种体内抗病毒的方法。总体目标是验证这些目标中的一个或多个的降级情况
具有高天然抵抗力的抗病毒战略,并将一流降解物作为领先的
抗病毒药物的开发。在追求这一目标的过程中,我们还将建立重要的概念证明和
为更广泛地开发针对其他病毒病原体的抗病毒降解剂奠定了基础。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
NATHANAEL Schiander GRAY其他文献
NATHANAEL Schiander GRAY的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('NATHANAEL Schiander GRAY', 18)}}的其他基金
Targeting CDK7 in CCNE1-amplified Ovarian Cancer
CCNE1 扩增的卵巢癌中靶向 CDK7
- 批准号:
10367792 - 财政年份:2022
- 资助金额:
$ 81.09万 - 项目类别:
Targeting CDK7 in CCNE1-amplified Ovarian Cancer
CCNE1 扩增的卵巢癌中靶向 CDK7
- 批准号:
10576332 - 财政年份:2022
- 资助金额:
$ 81.09万 - 项目类别:
Small molecule-induced degradation of dengue proteins as an antiviral strategy
小分子诱导的登革热蛋白降解作为抗病毒策略
- 批准号:
10052821 - 财政年份:2020
- 资助金额:
$ 81.09万 - 项目类别:
Validating the Flavivirus Envelope Protein as an Antiviral Target
验证黄病毒包膜蛋白作为抗病毒靶点
- 批准号:
10338189 - 财政年份:2020
- 资助金额:
$ 81.09万 - 项目类别:
Validating the Flavivirus Envelope Protein as an Antiviral Target
验证黄病毒包膜蛋白作为抗病毒靶点
- 批准号:
10578759 - 财政年份:2020
- 资助金额:
$ 81.09万 - 项目类别:
Validating the Flavivirus Envelope Protein as an Antiviral Target
验证黄病毒包膜蛋白作为抗病毒靶点
- 批准号:
10413666 - 财政年份:2020
- 资助金额:
$ 81.09万 - 项目类别:
Small molecule-induced degradation of dengue proteins as an antiviral strategy
小分子诱导的登革热蛋白降解作为抗病毒策略
- 批准号:
10661608 - 财政年份:2020
- 资助金额:
$ 81.09万 - 项目类别:
Small molecule-induced degradation of dengue proteins as an antiviral strategy
小分子诱导的登革热蛋白降解作为抗病毒策略
- 批准号:
10429876 - 财政年份:2020
- 资助金额:
$ 81.09万 - 项目类别:
Targeting the transcriptional and epigenetic landscape in chemo-refractory Small-Cell Lung Cancer
靶向化疗难治性小细胞肺癌的转录和表观遗传景观
- 批准号:
10174856 - 财政年份:2017
- 资助金额:
$ 81.09万 - 项目类别:
Development of covalent PIP4K2 inhibitors for the treatment of p53 deficient lung tumors
开发共价 PIP4K2 抑制剂用于治疗 p53 缺陷型肺部肿瘤
- 批准号:
8942703 - 财政年份:2015
- 资助金额:
$ 81.09万 - 项目类别:
相似海外基金
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 81.09万 - 项目类别:
Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 81.09万 - 项目类别:
Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 81.09万 - 项目类别:
Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 81.09万 - 项目类别:
Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 81.09万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 81.09万 - 项目类别:
Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 81.09万 - 项目类别:
Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 81.09万 - 项目类别:
Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
- 批准号:
23K00129 - 财政年份:2023
- 资助金额:
$ 81.09万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
- 批准号:
2883985 - 财政年份:2023
- 资助金额:
$ 81.09万 - 项目类别:
Studentship














{{item.name}}会员




