Small Molecule Protease Inhibitors against MERS-CoV
针对中东呼吸综合征冠状病毒的小分子蛋白酶抑制剂
基本信息
- 批准号:10396522
- 负责人:
- 金额:$ 72.86万
- 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:2018-05-15 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:Adverse effectsAffectAntiviral AgentsBinding ProteinsBiochemicalBiological AssayBiological AvailabilityBioterrorismCategory C pathogenCell Culture TechniquesCellsCoronavirusCoronavirus InfectionsDevelopmentDipeptidyl PeptidasesDipeptidyl-Peptidase IVDisease OutbreaksDisease ProgressionDrug DesignDrug KineticsElementsEnzymesFeline CoronavirusFeline infectious peritonitis virusFelis catusGoalsHealthHumanImmuneIn VitroInvestigational New Drug ApplicationKnock-inKnock-in MouseLeadMeasuresMediatingMetabolismMiddle EastMiddle East Respiratory SyndromeMiddle East Respiratory Syndrome CoronavirusModelingMorbidity - disease rateMusNational Institute of Allergy and Infectious DiseaseOralPapainPathogenesisPeptide HydrolasesPeritonitisPermeabilityPharmaceutical ChemistryPharmaceutical PreparationsPharmacologyPlasmaPlasma ProteinsPolyproteinsPreventionPreventiveProcessPropertyProtease InhibitorProteinsProteolytic ProcessingPublic HealthRNA VirusesReportingResearchRespiratory DiseaseSARS coronavirusSeriesSiteSolubilitySouth KoreaStructureStructure-Activity RelationshipTestingTherapeuticTimeVaccinesViralVirulentVirusVirus ReplicationX-Ray Crystallographyanaloganti-viral efficacyantiviral drug developmentbasebetacoronaviruschemical stabilitycomputer studiescoronavirus receptorcytotoxicitydesigndrug candidatein vivoinhibitorlead optimizationlead serieslipophilicitymortalitymouse modelnovelpiperidinepre-clinicalprocess optimizationprogramspublic health emergencyresistance mechanismsmall moleculesmall molecule therapeuticsspectroscopic surveytherapeutic targettransmission processviral resistance
项目摘要
PROJECT SUMMARY
Since the unexpected emergence of Middle East Respiratory Syndrome coronavirus (MERS-CoV) in 2013, the
ongoing outbreaks of MERS in the Middle East and the potential for global transmission of MERS, exemplified
by an outbreak in South Korea in 2015, have underscored the urgent need for effective preventive and
therapeutic measures against this highly virulent coronavirus. MERS-CoV expresses two polyproteins that
undergo proteolytic processing by two virus-encoded proteases, a 3C-like protease (3CLpro) and a papain-like
protease, to generate functionally active proteins. MERS-CoV 3CLpro processes the majority of the cleavage
sites on the polyproteins and is essential for viral replication, making it an attractive therapeutic target. A series
of potent dipeptidyl inhibitors of the 3CLpro of coronaviruses including MERS-CoV and infectious peritonitis
coronavirus (FIPV), a highly virulent feline coronavirus, have been generated. Using FIPV as a model, it was
demonstrated that the lead compound for FIPV reverses the progression of fatal FIP in experimentally or
naturally infected cats. Since FIP disease progression is quite rapid and its pathogenesis primarily immune-
mediated, features shared by MERS-CoV, it was hypothesized that a viral protease inhibitor could reverse the
pathogenesis of MERS-CoV in affected hosts. Using a structure-guided approach, the anti-FIPV compound
was structurally modified resulting in the identification of piperidine-derived lead compounds that were found to
be highly effective against MERS-CoV. Thus, the primary goal of this R01 application is the identification of an
in-vivo validated MERS-CoV preclinical candidate by conducting an array of basic and applied studies. Four
aims are proposed to achieve this objective. Specific Aim 1. Optimize the piperidine-derived lead series of
MERS-CoV 3CLpro inhibitors by iterative medicinal chemistry and structure-based drug design. Specific Aim 2.
Conduct in vitro efficacy, biochemical, mechanistic, structural, spectroscopic, and computational studies to
prioritize analogs, elucidate the mechanism of action, and accelerate the optimization process. Specific Aim 3.
Evaluate the physicochemical properties, ADMET, PK, and oral bioavailability of optimized leads. Specific Aim
4. Determine in vivo efficacy of optimized leads in mouse models of MERS-CoV infection. The ultimate long
term goal of this program is the development of antiviral therapeutics for MERS by advancing a drug candidate
through the stage of filing for an investigational new drug (IND) application.
项目摘要
自2013年中东呼吸综合征冠状病毒(MERS-CoV)意外出现以来,
中东地区正在爆发的MERS疫情以及MERS全球传播的可能性,
2015年在韩国爆发,强调了有效预防和
针对这种高毒性冠状病毒的治疗措施。MERS-CoV表达两种多蛋白,
通过两种病毒编码的蛋白酶进行蛋白水解加工,3C样蛋白酶(3CLpro)和木瓜蛋白酶样蛋白酶(3CLpro)。
蛋白酶,以产生功能活性蛋白。MERS-CoV 3CLpro处理大部分切割
多聚蛋白上的位点,是病毒复制所必需的,使其成为有吸引力的治疗靶点。一系列
冠状病毒(包括MERS-CoV和感染性腹膜炎)3CLpro的有效二肽基抑制剂
已经产生了一种高毒性猫冠状病毒(FIPV)。使用FIPV作为模型,
证明FIPV的先导化合物在实验或临床试验中逆转了致死性FIP的进展,
自然感染的猫。由于FIP疾病进展相当迅速,其发病机制主要是免疫-
由于MERS-CoV具有共同的介导的特征,因此假设病毒蛋白酶抑制剂可以逆转MERS-CoV的表达,
MERS-CoV在受影响宿主中的发病机制。使用结构指导的方法,抗FIPV化合物
结构上进行了修改,导致识别哌啶衍生的先导化合物,发现
对中东呼吸综合征病毒非常有效。因此,此R 01应用程序的主要目标是识别
通过进行一系列基础和应用研究,体内验证MERS-CoV临床前候选物。四
提出了实现这一目标的目标。具体目标1.优化哌啶衍生的铅系列
MERS-CoV 3CLpro抑制剂通过迭代药物化学和基于结构的药物设计。具体目标2。
进行体外功效、生化、机理、结构、光谱和计算研究,
确定类似物的优先顺序,阐明作用机制,并加速优化过程。具体目标3。
评价优化电极导线的理化性质、ADMET、PK和口服生物利用度。具体目标
4.在MERS-CoV感染的小鼠模型中确定优化的引线的体内功效。最长的
该计划的长期目标是通过开发候选药物来开发MERS的抗病毒治疗方法
通过提交研究性新药(IND)申请的阶段。
项目成果
期刊论文数量(5)
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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Kyeong-Ok Chang其他文献
Kyeong-Ok Chang的其他文献
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{{ truncateString('Kyeong-Ok Chang', 18)}}的其他基金
Small Molecule Inhibitors Against 3C-Like Protease of SARS-CoV-2
针对 SARS-CoV-2 3C 样蛋白酶的小分子抑制剂
- 批准号:
10670145 - 财政年份:2021
- 资助金额:
$ 72.86万 - 项目类别:
Small Molecule Inhibitors Against 3C-Like Protease of SARS-CoV-2
针对 SARS-CoV-2 3C 样蛋白酶的小分子抑制剂
- 批准号:
10238615 - 财政年份:2021
- 资助金额:
$ 72.86万 - 项目类别:
Small Molecule Inhibitors Against 3C-Like Protease of SARS-CoV-2
针对 SARS-CoV-2 3C 样蛋白酶的小分子抑制剂
- 批准号:
10463664 - 财政年份:2021
- 资助金额:
$ 72.86万 - 项目类别:
Small Molecule Protease Inhibitors against MERS-CoV
针对中东呼吸综合征冠状病毒的小分子蛋白酶抑制剂
- 批准号:
9918846 - 财政年份:2018
- 资助金额:
$ 72.86万 - 项目类别:
Development of Novel Therapeutic Agents for Norovirus Infection
诺如病毒感染新型治疗药物的开发
- 批准号:
8432063 - 财政年份:2009
- 资助金额:
$ 72.86万 - 项目类别:
Development of Novel Therapeutic Agents for Norovirus Infection
诺如病毒感染新型治疗药物的开发
- 批准号:
7782775 - 财政年份:2009
- 资助金额:
$ 72.86万 - 项目类别:
Development of Novel Therapeutic Agents for Norovirus Infection
诺如病毒感染新型治疗药物的开发
- 批准号:
8029576 - 财政年份:2009
- 资助金额:
$ 72.86万 - 项目类别:
Development of Novel Therapeutic Agents for Norovirus Infection
诺如病毒感染新型治疗药物的开发
- 批准号:
7642940 - 财政年份:2009
- 资助金额:
$ 72.86万 - 项目类别:
Development of Novel Therapeutic Agents for Norovirus Infection
诺如病毒感染新型治疗药物的开发
- 批准号:
8213750 - 财政年份:2009
- 资助金额:
$ 72.86万 - 项目类别:
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