Small Molecule Inhibitors Against 3C-Like Protease of SARS-CoV-2
Small Molecule Inhibitors Against 3C-Like Protease of SARS-CoV-2
批准号:
10463664
负责人:
Kyeong-Ok Chang
金额:
$73.5万
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
项目状态:
未结题
起止时间:
2021-08-06 至 2026-07-31
关键词:
2019-nCoVACE2AdenovirusesAdoptedAnimal ModelAnimalsAntiviral AgentsAreaBackBindingBiochemicalBiological AssayCOVID-19COVID-19 susceptibilityCOVID-19 treatmentCell Culture TechniquesCellsChemicalsChinaCommon ColdComplexCoronavirusCoronavirus InfectionsCrystallizationDevelopmentDiseaseDisease OutbreaksDrug DesignDrug TargetingElementsEnzymesFamilyFeline CoronavirusGenomeGoalsHistopathologyHumanIn VitroK-18 conjugateKnock-inKnock-in MouseLeadLungMeasuresMiddle East Respiratory Syndrome CoronavirusModelingMolecular ConformationMusNorovirusOutcomePapainPathogenicityPeptide HydrolasesPermeabilityPharmaceutical ChemistryPharmaceutical PreparationsPharmacologyPolyproteinsPreventiveProcessProtease InhibitorPublic HealthRNA VirusesResearchResolutionRespiratory DiseaseRiskRoentgen RaysSARS coronavirusSARS-CoV-2 genomeSARS-CoV-2 infectionSARS-CoV-2 inhibitorSARS-CoV-2 proteaseSeriesStructureStructure-Activity RelationshipTherapeuticTimeTransgenic OrganismsUpper Respiratory InfectionsVaccinesViralVirusVirus Replicationanaloganti-viral efficacyantiviral drug developmentbaseclinical candidateclinical developmentclinical efficacydesigndrug candidatedrug developmentefficacy studyhuman coronavirusimprovedin vivoindexinginhibitorlead optimizationlead seriesmouse modelnovelpre-clinicalpreclinical studyreceptorrespiratoryscaffoldscreeningsmall molecule inhibitortherapy development
中文摘要
项目总结
人类冠状病毒通常会引起普通感冒,这是一种轻微的上呼吸道疾病,然而,
新的人类冠状病毒感染与严重呼吸道疾病的暴发周期性地出现在
动物。这些病毒包括严重急性呼吸道冠状病毒(SARS-CoV)、中东呼吸综合征
冠状病毒(MERS-CoV),以及最近的SARS-CoV-2,2019年冠状病毒病的病原体
(新冠肺炎)。目前,没有获得许可的疫苗或抗病毒药物来对抗这些病毒,这突显了
迫切需要制定预防和治疗冠状病毒的措施。冠状病毒
基因组编码大的多聚蛋白,这些蛋白由一个类似3C的蛋白酶(3CLpro)和一个类似木瓜的酶处理
蛋白酶。这两种酶对病毒复制都是必不可少的,使它们成为药物开发的有吸引力的目标。
我们在这一领域的尝试已经发现了多种病毒的广谱抑制剂,包括
编码3CLPro的冠状病毒和诺如病毒,以及通过一种
猫冠状病毒3CLPro抑制剂。最近,我们已经证明了一种二肽基系列化合物
在细胞培养中有效抑制包括MERS-CoV和SARS-CoV-2在内的人类冠状病毒,并在体内展示
DPP4-KI小鼠MERS冠状病毒感染模型的疗效。这些化合物的抗病毒靶点是
从SARS-CoV、SARS-CoV和SARS-CoV获得高分辨晶体结构3CLPro-抑制剂复合体的验证
CoV-2和MERS-CoV。我们在此假设,已识别的系列可以作为
SARS-CoV-2特异性抗病毒药物的研究进展拟议研究的直接和总体目标是
进一步优化已鉴定的SARS-CoV-2先导抑制剂的药理活性PK参数
3CLPRO和体内抗SARS-CoV-2效果的演示。我们研究的预期结果是
选择一种临床前候选化合物(和1-2种备用化合物),该化合物非常适合进行进一步研究
临床前研究,最终导致新冠肺炎特异性抗病毒疗法的开发。
英文摘要
PROJECT SUMMARY
Human coronaviruses generally cause the common cold, a mild upper respiratory illness, however, global
outbreaks of new human coronavirus infections with severe respiratory disease have periodically emerged from
animals. These include Severe Acute Respiratory coronavirus (SARS-CoV), Middle East respiratory syndrome
coronavirus (MERS-CoV) and, most recently, SARS-CoV-2, the causative agent of coronavirus disease 2019
(COVID-19). Currently, there are no licensed vaccines or antiviral drugs against these viruses, underscoring an
urgent need for the development of preventive and therapeutic measures against coronaviruses. Coronavirus
genomes encode large polyproteins which are processed by a 3C-like protease (3CLpro) and a papain-like
protease. Both proteases are essential for viral replication, making them attractive targets for drug development.
Our foray in this area has resulted in the discovery of broad-spectrum inhibitors of multiple viruses, including
coronaviruses and noroviruses that encode 3CLpro, as well as the first demonstration of clinical efficacy by a
feline coronavirus 3CLpro inhibitor. Recently, we have demonstrated that a dipeptidyl series of compounds
potently inhibit human coronaviruses, including MERS-CoV and SARS-CoV-2 in cell culture, and display in vivo
efficacy in the DPP4-KI mouse model of MERS-CoV infection. The antiviral target of the compounds was
validated by obtaining high resolution crystal structures 3CLpro-inhibitor complexes from SARS-CoV, SARS-
CoV-2 and MERS-CoV. We hypothesize herein that the identified series can serve as a launching pad for the
development of SARS-CoV-2-specific antivirals. The immediate and overarching goal of the proposed studies is
to further optimize the pharmacological activity PK parameters of identified lead inhibitors of SARS-CoV-2
3CLpro and the demonstration of in vivo efficacy against SARS-CoV-2. The expected outcome of our studies is
the selection of a preclinical candidate (and 1-2 backup compounds) that is well-suited to conducting further
preclinical studies, ultimately leading to the development of a COVID-19-specific antiviral therapeutic.
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Small Molecule Inhibitors Against 3C-Like Protease of SARS-CoV-2
-
批准号:10670145
-
项目类别:
-
资助金额:$73.5万
-
财政年份:2021
-
负责人:Kyeong-Ok Chang
-
依托单位:
Small Molecule Inhibitors Against 3C-Like Protease of SARS-CoV-2
-
批准号:10238615
-
项目类别:
-
资助金额:$77.4万
-
财政年份:2021
-
负责人:Kyeong-Ok Chang
-
依托单位:
Small Molecule Protease Inhibitors against MERS-CoV
-
批准号:9918846
-
项目类别:
-
资助金额:$73.29万
-
财政年份:2018
-
负责人:Kyeong-Ok Chang
-
依托单位:
Small Molecule Protease Inhibitors against MERS-CoV
-
批准号:10396522
-
项目类别:
-
资助金额:$72.86万
-
财政年份:2018
-
负责人:Kyeong-Ok Chang
-
依托单位:
Development of Novel Therapeutic Agents for Norovirus Infection
-
批准号:8432063
-
项目类别:
-
资助金额:$89.56万
-
财政年份:2009
-
负责人:Kyeong-Ok Chang
-
依托单位:
REPLICATION OF NOROVIRUSES IN CELL CULTURE
-
批准号:7959698
-
项目类别:
-
资助金额:$25.35万
-
财政年份:2009
-
负责人:Kyeong-Ok Chang
-
依托单位:
Development of Novel Therapeutic Agents for Norovirus Infection
-
批准号:7782775
-
项目类别:
-
资助金额:$102.8万
-
财政年份:2009
-
负责人:Kyeong-Ok Chang
-
依托单位:
Development of Novel Therapeutic Agents for Norovirus Infection
-
批准号:8029576
-
项目类别:
-
资助金额:$100.6万
-
财政年份:2009
-
负责人:Kyeong-Ok Chang
-
依托单位:
Development of Novel Therapeutic Agents for Norovirus Infection
-
批准号:7642940
-
项目类别:
-
资助金额:$101.78万
-
财政年份:2009
-
负责人:Kyeong-Ok Chang
-
依托单位:
Development of Novel Therapeutic Agents for Norovirus Infection
-
批准号:8213750
-
项目类别:
-
资助金额:$95.28万
-
财政年份:2009
-
负责人:Kyeong-Ok Chang
-
依托单位:
REPLICATION OF NOROVIRUSES IN CELL CULTURE
-
批准号:7720553
-
项目类别:
-
资助金额:$24.28万
-
财政年份:2008
-
负责人:Kyeong-Ok Chang
-
依托单位:
REPLICATION OF NOROVIRUSES IN CELL CULTURE
-
批准号:7609903
-
项目类别:
-
资助金额:$16.95万
-
财政年份:2007
-
负责人:Kyeong-Ok Chang
-
依托单位:
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