High throughput screening of orthosteric inhibitors of flavivirus protease
黄病毒蛋白酶正构抑制剂的高通量筛选
基本信息
- 批准号:10376239
- 负责人:
- 金额:$ 55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-02-15 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeActive SitesAddressAffectAffinityAnimalsAntiviral AgentsAntiviral TherapyArbovirusesAreaBindingBiological AssayBiological AvailabilityBiological ModelsCell Culture TechniquesCellsChargeClinicalComplementComplexDengueDengue Hemorrhagic FeverDengue VirusDevelopment PlansDiseaseDisease OutbreaksDrug KineticsDrug TargetingEnsureEnzyme Inhibitor DrugsEnzyme InteractionEnzymesFlavivirusFlavivirus InfectionsFluorescence Resonance Energy TransferGenerationsGenesGoalsGrowthHepatitis CInfectionJapanese Encephalitis VaccinesJapanese encephalitis virusLeadLibrariesLifeLuciferasesMass VaccinationsMeningitisMicrocephalyModelingMultienzyme ComplexesMusMutagenesisMutationOutcome StudyPeptide HydrolasesPersonsPharmaceutical PreparationsPolyproteinsPopulations at RiskPreventionProtease InhibitorProteinsPublic HealthRenilla LuciferasesRepliconResearchResistanceResourcesSiteSolidStructure-Activity RelationshipSystemTechnologyTestingTick-Borne Encephalitis VirusToxic effectToxicity TestsVaccinatedVaccinesVariantViralViral GenomeViral PhysiologyViral ProteinsVirusVirus AssemblyVirus ReplicationWest Nile EncephalitisWest Nile virusWorkYellow fever virusZIKAZika Virusanti-viral efficacyantiviral drug developmentarthropod-bornebaseburden of illnesscombatdrug developmentdrug discoveryefficacy evaluationfightinghigh throughput screeninghuman diseasehuman pathogenin vivoinhibitorinnovationnanomolarnovelpublic health prioritiesscreeningsmall molecule librariestherapeutic targettherapy designtoolvaccine developmentviral resistancevirology
项目摘要
Project Summary/Abstract:
Many flaviviruses such as Dengue virus, Zika virus, West Nile virus, and Yellow Fever virus
cause significant human diseases. However, no clinically approved antiviral therapy is available
for treatment of flavivirus infections. Therefore, the development of vaccines and antiviral agents
for prevention and treatment of flavivirus infections is a clear public health priority. The long-
range goal of this proposal is to address this need by developing a new system to identify,
screen and validate a class of potential flavivirus inhibitors, and successfully identify and
analyze candidate compounds that show promise in disrupting viral survival.
During flaviviral infection of the host cell, a single viral polyprotein is synthesized from the viral
genome. This polyprotein is cleaved into its component proteins by a combination of host cell
proteases and a two-component viral protease, encoded in genes NS2B and NS3. The function
of this viral protease is indispensable for virus assembly and replication. The objectives of this
project are to develop innovative high throughput screening strategies to identify and
characterize compounds that orthosterically inhibit the function of the critical protease NS2B-
NS3.
To achieve project objectives, in Specific Aim 1, we will develop and perform novel high-
throughput screening primary, secondary, and tertiary assays capable of screening large
chemical libraries to identify orthosteric inhibitors. In Specific Aim 2, after optimizing these
assays, we will perform large-scale HTS to screen a compound library of >400,000 compounds
for potential protease inhibitor candidates, employing five levels of screening to fully eliminate
false positives. In Specific Aim 3, we will evaluate the efficacy of the resulting candidate
compounds for their capacity to block protease activity, and determined their modes of actions.
Lead compounds against the protease will be tested for cellular toxicity, reduction of flavivirus
titer in cell culture, resistant variants, and limited structure-activity relationship. We will ultimately
test the toxicity, pharmacokinetics, and efficacy in live animals for the most potent compounds.
We anticipate the outcome of this study will be the generation of crucial new information on
flavivirus inhibitor-enzyme interaction at structurally significant sites. This creates the potential
for identifying novel classes of flaviviral inhibitors, suitable for addressing the global public
health need for new antiviral agents to fight flaviviruses.
项目概要/摘要:
许多黄病毒,如登革热病毒、寨卡病毒、西尼罗河病毒和黄热病病毒
导致严重的人类疾病。然而,没有临床批准的抗病毒治疗是可用的
用于治疗黄病毒感染。因此,疫苗和抗病毒剂的开发
预防和治疗黄病毒感染显然是公共卫生的优先事项。很长的-
本提案的范围目标是通过开发一个新系统来满足这一需求,
筛选并验证了一类潜在的黄病毒抑制剂,并成功鉴定和
分析有望破坏病毒存活的候选化合物。
在宿主细胞的黄病毒感染期间,从病毒多聚蛋白合成单个病毒多聚蛋白。
基因组这种多聚蛋白被宿主细胞的组合切割成其组成蛋白。
蛋白酶和双组分病毒蛋白酶,其在基因NS 2B和NS 3中编码。功能
这种病毒蛋白酶是病毒组装和复制所不可缺少的。这一目标
项目是开发创新的高通量筛选策略,以确定和
表征正构抑制关键蛋白酶NS 2B-的功能的化合物,
NS3。
为了实现项目目标,在具体目标1中,我们将开发和执行新的高-
通量筛选一级、二级和三级试验,能够筛选大的
化学文库来鉴定正构抑制剂。在具体目标2中,在优化这些之后,
我们将进行大规模的HTS,以筛选超过40万种化合物的化合物库。
对于潜在的蛋白酶抑制剂候选物,采用五个级别的筛选,以完全消除
假阳性在具体目标3中,我们将评估最终候选人的有效性
化合物阻断蛋白酶活性的能力,并确定其作用模式。
将测试针对蛋白酶的先导化合物的细胞毒性、黄病毒减少
细胞培养物中的滴度、抗性变体和有限的结构-活性关系。最终肯定我们会
在活体动物中测试最有效化合物的毒性、药代动力学和功效。
我们预计这项研究的结果将是产生关键的新信息,
在结构上重要的位点上的黄病毒介导物-酶相互作用。这就创造了
用于鉴定新的黄病毒抑制剂类别,适用于全球公众
健康需要新的抗病毒药物来对抗黄病毒。
项目成果
期刊论文数量(12)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Calcimycin Inhibits Cryptococcus neoformans In Vitro and In Vivo by Targeting the Prp8 Intein Splicing.
- DOI:10.1021/acsinfecdis.2c00137
- 发表时间:2022-09-09
- 期刊:
- 影响因子:5.3
- 作者:Tharappel, Anil Mathew;Li, Zhong;Zhu, Yan Chun;Wu, Xiangmeng;Chaturvedi, Sudha;Zhang, Qing-Yu;Li, Hongmin
- 通讯作者:Li, Hongmin
Erythrosin B is a potent and broad-spectrum orthosteric inhibitor of the flavivirus NS2B-NS3 protease.
- DOI:10.1016/j.antiviral.2017.12.018
- 发表时间:2018-03
- 期刊:
- 影响因子:7.6
- 作者:Li Z;Sakamuru S;Huang R;Brecher M;Koetzner CA;Zhang J;Chen H;Qin CF;Zhang QY;Zhou J;Kramer LD;Xia M;Li H
- 通讯作者:Li H
Methylene blue is a potent and broad-spectrum inhibitor against Zika virus in vitro and in vivo.
- DOI:10.1080/22221751.2020.1838954
- 发表时间:2020-12
- 期刊:
- 影响因子:13.2
- 作者:Li Z;Lang Y;Sakamuru S;Samrat S;Trudeau N;Kuo L;Rugenstein N;Tharappel A;D'Brant L;Koetzner CA;Hu S;Zhang J;Huang R;Kramer LD;Butler D;Xia M;Li H
- 通讯作者:Li H
In vitro and in vivo characterization of erythrosin B and derivatives against Zika virus.
- DOI:10.1016/j.apsb.2021.10.017
- 发表时间:2022-04
- 期刊:
- 影响因子:14.5
- 作者:Li, Zhong;Xu, Jimin;Lang, Yuekun;Wu, Xiangmeng;Hu, Saiyang;Samrat, Subodh Kumar;Tharappel, Anil M.;Kuo, Lili;Butler, David;Song, Yongcheng;Zhang, Qing-Yu;Zhou, Jia;Li, Hongmin
- 通讯作者:Li, Hongmin
JMX0207, a Niclosamide Derivative with Improved Pharmacokinetics, Suppresses Zika Virus Infection Both In Vitro and In Vivo.
- DOI:10.1021/acsinfecdis.0c00217
- 发表时间:2020-10-09
- 期刊:
- 影响因子:5.3
- 作者:Li Z;Xu J;Lang Y;Fan X;Kuo L;D'Brant L;Hu S;Samrat SK;Trudeau N;Tharappel AM;Rugenstein N;Koetzner CA;Zhang J;Chen H;Kramer LD;Butler D;Zhang QY;Zhou J;Li H
- 通讯作者:Li H
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HONGMIN LI其他文献
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{{ truncateString('HONGMIN LI', 18)}}的其他基金
Development of Inhibitors Targeting Flavivirus Methyltransferase
黄病毒甲基转移酶抑制剂的开发
- 批准号:
10636605 - 财政年份:2023
- 资助金额:
$ 55万 - 项目类别:
Discovery of therapeutics against Cryptococcosis by Repurposing Pharmaceutical Libraries
通过重新利用药物库发现隐球菌病的治疗方法
- 批准号:
10308245 - 财政年份:2019
- 资助金额:
$ 55万 - 项目类别:
High throughput screening of the Prp8 intein splicing inhibitors for pathogenic fungi
病原真菌 Prp8 内含肽剪接抑制剂的高通量筛选
- 批准号:
10319642 - 财政年份:2018
- 资助金额:
$ 55万 - 项目类别:
High throughput screening of orthosteric inhibitors of flavivirus protease
黄病毒蛋白酶正构抑制剂的高通量筛选
- 批准号:
10318299 - 财政年份:2018
- 资助金额:
$ 55万 - 项目类别:
High throughput screening of the Prp8 intein splicing inhibitors for pathogenic fungi
病原真菌 Prp8 内含肽剪接抑制剂的高通量筛选
- 批准号:
10382470 - 财政年份:2018
- 资助金额:
$ 55万 - 项目类别:
High throughput screening of orthosteric inhibitors of flavivirus protease
黄病毒蛋白酶正构抑制剂的高通量筛选
- 批准号:
9538444 - 财政年份:2017
- 资助金额:
$ 55万 - 项目类别:
Mechanism of MALT1 Regulation by a Novel Ubiquitin Ligase
新型泛素连接酶调节 MALT1 的机制
- 批准号:
9053450 - 财政年份:2015
- 资助金额:
$ 55万 - 项目类别:
Mechanism of MALT1 Regulation by a Novel Ubiquitin Ligase
新型泛素连接酶调节 MALT1 的机制
- 批准号:
8821943 - 财政年份:2015
- 资助金额:
$ 55万 - 项目类别:
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