Novel small-molecule inhibitors of SARS-CoV-2 protease
Novel small-molecule inhibitors of SARS-CoV-2 protease
批准号:
10200270
负责人:
Yongcheng Song
金额:
$44.0万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-12-01 至 2023-11-30
关键词:
2019-nCoVAldehydesAmidesAnti-Infective AgentsAntineoplastic AgentsAntiviral AgentsBindingBiochemicalBiologicalBiological AvailabilityCOVID-19COVID-19 treatmentCaspaseCellsCessation of lifeChemicalsChinaChronic lung diseaseCleaved cellClinical TrialsCoronavirus InfectionsCoughingCountryCysteineDNA-Directed RNA PolymeraseDangerousnessDiabetes MellitusDisease OutbreaksDrug TargetingEnzyme InhibitionEstersFDA Emergency Use AuthorizationFatality rateFatigueFeverGrantImmunocompromised HostInfectionInfluenzaInfluenza A Virus, H1N1 SubtypeLeadLibrariesLifeLungLung diseasesMedicalMetabolicModern 1601-historyMultiple Organ FailureNonstructural ProteinObesityOrgan failurePapainPatientsPeptide HydrolasesPeptidesPharmaceutical ChemistryPharmaceutical PreparationsPharmacologyPilot ProjectsPneumoniaPolymerasePolyproteinsProteinsPrunella vulgarisRNA VirusesReportingRoentgen RaysSARS coronavirusSARS-CoV-2 inhibitorSepsisSeriesSevere Acute Respiratory SyndromeSiteStructure-Activity RelationshipSupportive careSymptomsTestingTimeVaccinesViralViral ProteinsVirus ReplicationX-Ray Crystallographybasechymotrypsin Acytotoxicitydesigndrug developmenthigh riskhuman old age (65+)improvedin vivoinhibitor/antagonistnovelnovel coronavirusnovel therapeuticspandemic diseasepathogenpeptidomimeticsremdesivirreproductivescreeningsmall molecule inhibitorsuccessswine flutherapeutically effectiveviral RNA
中文摘要
这个项目的总体目标是结合药物化学,x射线晶体学,
英文摘要
The overall objective of this project is to use a combination of medicinal chemistry, X-ray crystallography,
biochemical and biological activity testing to develop potent, drug-like inhibitors of the main protease (Mpro) of
SARS-CoV-2 (SARS-2), a novel coronavirus that causes an outbreak of a serious pulmonary disease COVID-
19 (coronavirus disease 2019). SARS-2 has emerged in Wuhan, China and soon spread to >210 countries
worldwide. WHO has declared COVID-19 a global pandemic in March 11, 2020. As of early June, SARS-2 has
infected ~7 million people (confirmed cases) globally, including ~2 million cases in the US. These numbers are
rapidly growing everyday. SARS-2 is highly contagious. While most patients (81%) infected with SARS-2 show
relatively mild symptoms, life-threatening severe illness, including severe pneumonia, sepsis and organ failure,
can occur at a significantly higher risk for people at age of ≥65 years and people with serious underlying
medical conditions. SARS-2 has caused ~400,000 deaths globally including >110,000 in the US (as of early
June, 2020), which makes it one of the most dangerous pathogens in modern history. There is therefore a
pressing need to find effective therapeutics and vaccines for SARS-2 infection. The main protease (Mpro) of
SARS-2 is essential for the viral replication and therefore a drug target. Specific Aim 1 is to use ration inhibitor
design, medicinal chemistry and structure-activity relationship (SAR) studies to find more potent inhibitors of
SARS-2 Mpro. Specific Aim 2 is to perform enzyme inhibition, X-ray crystallographic and other
biochemical/physical studies to characterize compounds made in Aim 1, which will be used to guide rational
design and SAR studies in Aim 1 to find compounds with improved potency. Specific Aim 3 is to perform
cytotoxicity and cellular antiviral activity testing of selected potent inhibitors of SARS-2 Mpro, in order to find
non-cytotoxic, potent antiviral compound against SARS-2 and -1 infections. Success of this pilot project would
lead to small-molecule inhibitors with improved potency that can strongly inhibit SARS-2 replication. In
addition, X-ray crystallography and other biochemical/physical studies would reveal the inhibitor-Mpro
interactions. These compounds would serve as novel pharmacological leads for further drug development
targeting SARS-2 and other coronavirus infection.
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