VPS34 inhibitors as SARS-CoV-2 antivirals
VPS34 抑制剂作为 SARS-CoV-2 抗病毒药物
基本信息
- 批准号:10238577
- 负责人:
- 金额:$ 1.31万
- 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 2021-11-15
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-Kinase2019-nCoVAcyl Coenzyme AAddressAntiviral AgentsAutophagocytosisBiological AssayCOVID-19COVID-19 patientCOVID-19 treatmentCell membraneCellsClinicalCoenzyme A LigasesCoronavirusCoronavirus InfectionsDataDevelopmentDiabetes MellitusEndoplasmic Reticulum Degradation PathwayEnzyme Inhibitor DrugsEnzymesExhibitsFDA approvedFatty-acid synthaseGenerationsGeneticGrowthHamstersHealthHumanImpairmentInfectionIntegration Host FactorsKnock-outLipidsMalignant NeoplasmsMeasuresMedicalMembraneMembrane BiologyMesocricetus auratusMetabolicMicroscopyModelingNatural ImmunityNonstructural ProteinObesityOralOrganellesOutcomePalmitatesPathway interactionsPharmacologyPhosphotransferasesPlayProteinsProteomicsRNA VirusesRNA chemical synthesisRegulationRepliconRoleSARS-CoV-2 infectionSiteSocietiesTestingTherapeuticTherapeutic InterventionTimeVesicleViralVirusVirus Replicationbasebetacoronaviruscytotoxicitydrug repurposingin vivoinhibitor/antagonistinnovationinsightinterestknock-downlipid metabolismlipid transportlong chain fatty acidmembernovelorlistatpandemic diseasephosphatidylinositol 3-phosphateremdesivirsmall moleculesmall molecule inhibitortargeted treatmenttherapeutic developmenttherapeutic targettraffickingtranscriptomicstriacsin Cviral RNA
项目摘要
Summary
SARS-CoV-2, a Betacoronavirus genus, is an enveloped positive-sense, RNA virus responsible
for a current pandemic. Because of its profound impact on society and human health there is an
urgent need to understand SARS-CoV-2 replication requirements and to identify therapeutic
strategies. Repurposing drugs developed for other purposes may provide a shortcut to therapeutic
development. The use of compounds known to target specific host factors may also elucidate key
pathways needed for virus replication. Coronavirus (CoV) replication involves multiple critical
interactions with host cell membranes. One of the most striking features of CoV infection is the
establishment of membrane-associated replication organelles that serve as the main sites of viral
RNA synthesis. The origin of these membrane organelles is incompletely understood. Because
the specific host pathways required for SARS-CoV-2 replication organelle formation are not
defined, we asked whether SARS-CoV-2 is susceptible to modulators of lipid metabolism by
assessing the sensitivity of the virus to VPS34 inhibitors of VPS34, a lipid kinase required for
autophagy and endosomal trafficking; Triacsin C, an inhibitor of long chain fatty acyl CoA
synthetase (ACSL) and Orlistat, an inhibitor of fatty acid synthase (FASN). Our preliminary data
indicate that inhibitors of VPS34 potently inhibited SARS-CoV-2 replication, whereas an FDA-
approved inhibitor of a different class of PI3K had minimal effect on replication. Targeting FASN
and ACSL also impairs SARS-CoV-2 replication. These data suggest that VPS34, ACSL and
FASN play important roles in replication center formation and virus growth and suggest these
enzymes as therapeutic targets. We will test the hypothesis that VPS34, ACSL and FASN are
critical for SARS-Cov-2 infection by evaluating additional small molecule inhibitors of these
enzymes and by measuring SARS-CoV-2 replication in genetic knockdowns or knockouts of these
host enzymes. We will define mechanisms of inhibition and test the hypothesis that generation
of membrane-associated viral replication centers will be disrupted. Finally, we will assess the in
vivo efficacy of VSP34 inhibitor PIK-III and systemically administered Orlistat in SARS-coV-2-
infected hamsters to evaluate the therapeutic potential of inhibitors of lipid metabolism.
摘要
SARS-CoV-2是一种β冠状病毒属,是一种有包膜的阳性RNA病毒
以应对当前的大流行。由于它对社会和人类健康的深刻影响,
迫切需要了解SARS-CoV-2复制要求并确定治疗方法
战略。为其他目的开发的药物的再利用可能为治疗提供一条捷径
发展。使用已知的针对特定宿主因子的化合物也可以阐明关键
病毒复制所需的途径。冠状病毒(CoV)复制涉及多个关键
与宿主细胞膜的相互作用。冠状病毒感染最显著的特征之一是
作为病毒主要部位的膜相关复制细胞器的建立
RNA合成。这些膜细胞器的起源尚不完全清楚。因为
SARS-CoV-2复制细胞器形成所需的特定宿主途径不是
定义,我们询问SARS-CoV-2是否对脂代谢调节剂易感,通过
评估病毒对Vps34抑制剂的敏感性,Vps34是一种脂酶,需要
自噬和内体运输;Triacsin C,长链脂肪酰辅酶A的抑制剂
脂肪酸合成酶(ACSL)和脂肪酸合成酶(FASN)抑制剂奥利司他。我们的初步数据
表明Vps34的抑制剂有效地抑制了SARS-CoV-2的复制,而FDA-
批准的另一类PI3K的抑制剂对复制的影响很小。目标FASN
ACSL还可抑制SARS-CoV-2的复制。这些数据表明,Vps34、ACSL和
FASN在复制中心的形成和病毒的生长中起着重要的作用,并提示这些
以酶为治疗靶点。我们将测试Vps34、ACSL和FASN是
通过评估其他小分子抑制剂对SARS-CoV-2感染的关键作用
并通过测量SARS-CoV-2在这些基因敲除或敲除中的复制
宿主酶。我们将定义抑制机制并检验生成的假设
膜相关病毒复制中心的一部分将被破坏。最后,我们将评估In
VSP34抑制剂PIK-III和全身应用奥利司他对SARS-CoV-2的体内疗效
以评估脂代谢抑制剂的治疗潜力。
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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Christopher F Basler其他文献
Sensing RNA virus infections
感知 RNA 病毒感染
- DOI:
10.1038/nchembio0107-20 - 发表时间:
2007-01-01 - 期刊:
- 影响因子:13.700
- 作者:
Christopher F Basler;Adolfo García-Sastre - 通讯作者:
Adolfo García-Sastre
Christopher F Basler的其他文献
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{{ truncateString('Christopher F Basler', 18)}}的其他基金
Understanding how the MERS Coronavirus protein ORF4b interactions with importin alpha modulate innate immunity
了解 MERS 冠状病毒蛋白 ORF4b 与 importin alpha 的相互作用如何调节先天免疫
- 批准号:
10289173 - 财政年份:2021
- 资助金额:
$ 1.31万 - 项目类别:
VPS34 inhibitors as SARS-CoV-2 antivirals
VPS34 抑制剂作为 SARS-CoV-2 抗病毒药物
- 批准号:
10534720 - 财政年份:2021
- 资助金额:
$ 1.31万 - 项目类别:
Understanding how the MERS Coronavirus protein ORF4b interactions with importin alpha modulate innate immunity
了解 MERS 冠状病毒蛋白 ORF4b 与 importin alpha 的相互作用如何调节先天免疫
- 批准号:
10438878 - 财政年份:2021
- 资助金额:
$ 1.31万 - 项目类别:
Small Molecule Inhibitors of Ebola Virus Polymerase Function
埃博拉病毒聚合酶功能的小分子抑制剂
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10534719 - 财政年份:2021
- 资助金额:
$ 1.31万 - 项目类别:
Understanding how the MERS Coronavirus protein ORF4b interactions with importin alpha modulate innate immunity
了解 MERS 冠状病毒蛋白 ORF4b 与 importin alpha 的相互作用如何调节先天免疫
- 批准号:
10536332 - 财政年份:2021
- 资助金额:
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Intersection Between Viral Translation and Innate Immunity in the Context of Filovirus Infection
丝状病毒感染背景下病毒翻译与先天免疫之间的交叉
- 批准号:
10593400 - 财政年份:2020
- 资助金额:
$ 1.31万 - 项目类别:
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丝状病毒感染背景下病毒翻译与先天免疫之间的交叉
- 批准号:
10425317 - 财政年份:2020
- 资助金额:
$ 1.31万 - 项目类别:
Intersection Between Viral Translation and Innate Immunity in the Context of Filovirus Infection
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- 批准号:
10214516 - 财政年份:2020
- 资助金额:
$ 1.31万 - 项目类别:
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