grant

Small Molecule Inhibitors Against 3C-Like Protease of SARS-CoV-2

Organization KANSAS STATE UNIVERSITYLocation MANHATTAN, UNITED STATESPosted 6 Aug 2021Deadline 31 Jan 2027
NIHUS FederalResearch GrantFY20252019 novel corona virus2019 novel coronavirus2019-nCoVACE2Acute NasopharyngitisAdenoviridaeAdenovirusesAdoptedAnimal ModelAnimal Models and Related StudiesAnimalsAnti-viral AgentsAntiproteasesAreaAssayBackBindingBioassayBiochemicalBiological AssayCOVID-19COVID-19 genomeCOVID-19 infectionCOVID-19 predispositionCOVID-19 susceptibilityCOVID-19 therapyCOVID-19 treatmentCOVID-19 virusCOVID-19 virus genomeCOVID-19 virus infectionCOVID-19 vulnerabilityCOVID19 genomeCOVID19 infectionCOVID19 virusCOVID19 virus genomeCV-19Cell BodyCell Culture TechniquesCellsChemicalsChinaCoV-2CoV2Common ColdComplexCoronaviridaeCoronaviridae InfectionsCoronavirusCoronavirus InfectionsCoronavirus Infectious Disease 2019Coronavirus disease 2019 predispositionCoronavirus disease 2019 susceptibilityCoronavirus disease 2019 vulnerabilityDevelopmentDiseaseDisorderDorsumDrug DesignDrug TargetingDrugsElementsEndopeptidase InhibitorsEnzyme GeneEnzymesEsteroproteasesFamilyFeline CoronavirusFeline Enteric CoronavirusGenomeGoalsHCoVHistopathologyHumanIn VitroK-18K-18 conjugateK18K18 combinationKI miceKnock-inKnock-in MouseLeadLicensingLungLung Respiratory SystemMERSMERS corona virusMERS coronavirusMERS coronavirus diseaseMERS virusMERS-CoVMERS-CoV diseaseMainland ChinaMeasuresMedicationMedicinal ChemistryMiceMice MammalsMiddle East Respiratory SyndromeMiddle East Respiratory Syndrome CoV diseaseMiddle East Respiratory Syndrome Corona VirusMiddle East Respiratory Syndrome CoronavirusMiddle East Respiratory Syndrome VirusMiddle East Respiratory Syndrome coronavirus diseaseMiddle East Respiratory Syndrome-CoVMiddle East Respiratory VirusMiddle East Respiratory coronavirusMiddle Eastern Respiratory SyndromeMiddle Eastern Respiratory Syndrome CoV diseaseMiddle Eastern Respiratory Syndrome Corona virusMiddle Eastern Respiratory Syndrome CoronavirusMiddle Eastern Respiratory Syndrome VirusMiddle Eastern Respiratory Syndrome coronavirus diseaseMiddle Eastern Respiratory Syndrome-CoVModelingModern ManMolecular ConfigurationMolecular ConformationMolecular InteractionMolecular StereochemistryMurineMusNorovirusNorwalk-like VirusesOrthocoronavirinaeOutcomePapainPathogenicityPb elementPeptidase InhibitorsPeptidasesPeptide Hydrolase InhibitorsPeptide HydrolasesPeptide Peptidohydrolase InhibitorsPermeabilityPharmaceutic ChemistryPharmaceutical ChemistryPharmaceutical PreparationsPolyproteinsPredisposed to COVID-19Predisposed to SARS-CoV-2Predisposed to Severe acute respiratory syndrome coronavirus 2PreventiveProcessProtease AntagonistsProtease GeneProtease InhibitorProteasesProteinase InhibitorsProteinasesProteolytic EnzymesPublic HealthRNA VirusesReceptor ProteinResearchResolutionRespiratory DiseaseRespiratory System DiseaseRespiratory System DisorderRoentgen RaysSARS Coronavirus 2 ProteaseSARS VirusSARS corona virusSARS corona virus 2SARS coronavirusSARS-Associated CoronavirusSARS-CO-V2SARS-COVID-2SARS-CoVSARS-CoV-1SARS-CoV-2SARS-CoV-2 genomeSARS-CoV-2 infectionSARS-CoV-2 inhibitorSARS-CoV-2 predispositionSARS-CoV-2 proteaseSARS-CoV-2 susceptibilitySARS-CoV-2 therapySARS-CoV-2 treatmentSARS-CoV-2 vulnerabilitySARS-CoV2SARS-CoV2 genomeSARS-CoV2 infectionSARS-Related CoronavirusSARS-associated corona virus 2SARS-associated coronavirus 2SARS-coronavirus-2SARS-related corona virus 2SARS-related coronavirus 2SARSCoV2SeriesSevere Acute Respiratory CoronavirusSevere Acute Respiratory Coronavirus 2Severe Acute Respiratory Distress Syndrome CoV 2Severe Acute Respiratory Distress Syndrome Corona Virus 2Severe Acute Respiratory Distress Syndrome Coronavirus 2Severe Acute Respiratory Syndrome CoV 2Severe Acute Respiratory Syndrome VirusSevere Acute Respiratory Syndrome corona virusSevere Acute Respiratory Syndrome coronavirusSevere Acute Respiratory Syndrome-associated coronavirus 2Severe Acute Respiratory Syndrome-related coronavirus 2Severe acute respiratory syndrome associated corona virus 2Severe acute respiratory syndrome coronavirus 2Severe acute respiratory syndrome coronavirus 2 infectionSevere acute respiratory syndrome coronavirus 2 inhibitorSevere acute respiratory syndrome coronavirus 2 predispositionSevere acute respiratory syndrome coronavirus 2 susceptibilitySevere acute respiratory syndrome coronavirus 2 vulnerabilitySevere acute respiratory syndrome related corona virus 2StructureStructure-Activity RelationshipTherapeuticTimeTransgenic OrganismsUpper Respiratory InfectionsUpper Respiratory Tract InfectionVaccinesViralVirusVirus ReplicationWuhan coronavirusX-RadiationX-Ray RadiationX-rayXrayanalogangiotensin converting enzyme 2angiotensin converting enzyme IIanti-viral compoundanti-viral developmentanti-viral drug developmentanti-viral drugsanti-viral efficacyanti-viral medicationanti-viral therapeuticanti-viral therapeutic developmentanti-viral therapy developmentanti-viralsantiviral developmentantiviral drug developmentantiviral therapeutic developmentantiviral therapy developmentblock SARS-CoV-2block severe acute respiratory syndrome coronavirus 2cell culturecell cultureschemical structure functionclinical developmentclinical efficacyconformationconformationalconformational stateconformationallyconformationscorona viruscoronavirus disease 2019coronavirus disease 2019 genomecoronavirus disease 2019 infectioncoronavirus disease 2019 therapycoronavirus disease 2019 treatmentcoronavirus disease 2019 viruscoronavirus disease 2019 virus genomecoronavirus disease-19coronavirus disease-19 viruscoronavirus infectious disease-19designdesigningdevelop therapydeveloping anti-viral agentdeveloping anti-viral drugdeveloping anti-viral therapeuticdeveloping anti-viral therapydeveloping antiviral agentdeveloping antiviral drugdeveloping antiviral therapeuticdeveloping antiviral therapydevelopmentaldrug candidatedrug developmentdrug/agentefficacy studyemergent outbreakemerging outbreakhCoV19heavy metal Pbheavy metal leadhuman CoVhuman corona virushuman coronavirusimprovedin vivoindexinginfected with COVID-19infected with COVID19infected with SARS-CoV-2infected with SARS-CoV2infected with coronavirus disease 2019infected with severe acute respiratory syndrome coronavirus 2inhibit SARS-CoV-2inhibit severe acute respiratory syndrome coronavirus 2inhibitorintervention developmentknockinknockin micelead optimizationlead seriesmetermodel of animalmouse modelmurine modelnCoV2new outbreaknovelnovel outbreakpharmacologicpre-clinicalpre-clinical studypreclinicalpreclinical studypredisposed to Coronavirus disease 2019receptorresolutionsrespiratoryrisk mitigationscaffoldscaffoldingscreeningscreeningssevere acute respiratory syndrome coronavirus 2 genomesevere acute respiratory syndrome coronavirus 2 proteasesevere acute respiratory syndrome coronavirus 2 therapysevere acute respiratory syndrome coronavirus 2 treatmentsevere acute respiratory syndrome-CoVsmall molecular inhibitorsmall molecule inhibitorstructural determinantsstructural factorsstructure function relationshipsusceptible to COVID-19susceptible to Coronavirus disease 2019susceptible to SARS-CoV-2susceptible to Severe acute respiratory syndrome coronavirus 2therapy developmenttransgenictreat COVID-19treat SARS-CoV-2treat coronavirus disease 2019treat severe acute respiratory syndrome coronavirus 2treatment developmentviral multiplicationviral replicationvirus multiplicationvulnerable to COVID-19vulnerable to Coronavirus disease 2019vulnerable to SARS-CoV-2vulnerable to Severe acute respiratory syndrome coronavirus 2
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Full Description

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.

Grant Number: 4R01AI161085-04
NIH Institute/Center: NIH
Principal Investigator: Kyeong-Ok Chang

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