grant
De Novo Design of Minibinder Antagonists for COVID-19 and Future Pandemics
Organization UNIVERSITY OF WASHINGTONLocation SEATTLE, UNITED STATESPosted 2 Aug 2021Deadline 31 Jul 2026
NIHUS FederalResearch GrantFY20252019 novel corona virus2019 novel coronavirus2019-nCoV2019-nCoV S protein2019-nCoV spike glycoprotein2019-nCoV spike proteinACE2ARDSAcuteAcute Respiratory DistressAcute Respiratory Distress SyndromeAdult ARDSAdult RDSAdult Respiratory Distress SyndromeAerosolsAffinityAnimalsAnti-InflammatoriesAnti-Inflammatory AgentsAnti-inflammatoryAnti-viral AgentsAntibodiesAvidityB cell differentiation factorB cell stimulating factor 2B-Cell Differentiation FactorB-Cell Differentiation Factor-2B-Cell Stimulatory Factor-2BCDFBSF-2BSF2Beta Proprotein Interleukin 1BindingBinding ProteinsBinding SitesCOVID crisisCOVID epidemicCOVID pandemicCOVID-19COVID-19 S proteinCOVID-19 associated deathCOVID-19 associated fatalityCOVID-19 associated mortalityCOVID-19 crisisCOVID-19 deathCOVID-19 epidemicCOVID-19 eraCOVID-19 fatalityCOVID-19 global health crisisCOVID-19 global pandemicCOVID-19 health crisisCOVID-19 induced deathCOVID-19 induced fatalityCOVID-19 induced mortalityCOVID-19 infectionCOVID-19 mortalityCOVID-19 pandemicCOVID-19 periodCOVID-19 public health crisisCOVID-19 related deathCOVID-19 related fatalityCOVID-19 related mortalityCOVID-19 spikeCOVID-19 spike glycoproteinCOVID-19 spike proteinCOVID-19 therapeuticsCOVID-19 therapyCOVID-19 treatmentCOVID-19 virusCOVID-19 virus infectionCOVID-19 yearsCOVID19 associated deathCOVID19 associated fatalityCOVID19 associated mortalityCOVID19 deathCOVID19 fatalityCOVID19 induced deathCOVID19 induced fatalityCOVID19 induced mortalityCOVID19 infectionCOVID19 mortalityCOVID19 related deathCOVID19 related fatalityCOVID19 related mortalityCOVID19 virusCV-19Capillary Leak SyndromeCell BodyCell Communication and SignalingCell SignalingCellsClinical Treatment MoabCo-StimulatorCoV emergenceCoV-2CoV2Combining SiteComputing MethodologiesCoronavirus Infectious Disease 2019CostimulatorCoupledCytokine ReceptorsDa Nang LungDevelopmentDiseaseDisease OutbreaksDisorderDrug CompoundingDrug KineticsDrug PreparationDrugsE coliE. coliEarly-Stage Clinical TrialsEndothelial CellsEpidermal Thymocyte Activating FactorEpithelial CellsEscherichia coliGeneticGlycoproteinsGoalsGolden HamstersGolden Syrian HamstersHPGFHepatocyte-Stimulating FactorHigh Affinity Interleukin-2 ReceptorHigh Performance ComputingHumanHybridoma Growth FactorIFN-beta 2IFNB2IL-1 betaIL-1 βIL-1-bIL-1βIL-2IL-2 ReceptorsIL-6IL1-BetaIL1-βIL1B ProteinIL1F2IL1RIL1R1IL1R1 geneIL1RAIL1βIL2 ProteinIL2 ReceptorsIL6 ProteinInfectionInflammatoryInflammatory ResponseInfluenza HAInfluenza HemagglutininInterleukin 1betaInterleukin 2Interleukin 2 PrecursorInterleukin 2 ReceptorInterleukin IIInterleukin-1 betaInterleukin-1βInterleukin-2Interleukin-6Interleukine 2Interleukine 2 PrecursorInterleukine IIInterleukinsIntracellular Communication and SignalingIntravenousK-18K-18 conjugateK18K18 combinationLeadLifeLigand Binding ProteinLigand Binding Protein GeneLymphocyte Mitogenic FactorMGI-2MedicationMesocricetus auratusMethodsMiceMice MammalsMissionMitogenic FactorModelingModern ManMolecular InteractionMonoclonal AntibodiesMurineMusMyeloid Differentiation-Inducing ProteinNational Institutes of HealthNebulizerOrgan failureOutbreaksOutcomePb elementPeptidesPharmaceutical PreparationsPharmacokineticsPhase 1 Clinical TrialsPhase I Clinical TrialsPlasmacytoma Growth FactorPreinterleukin 1 BetaProtein BindingProtein EngineeringProteinsProtocolProtocols documentationPublic HealthReactive SiteReceptor ProteinResearchRodent ModelRouteSARS corona virus 2SARS-CO-V2SARS-COVID-2SARS-CoV-2SARS-CoV-2 SSARS-CoV-2 S proteinSARS-CoV-2 associated deathSARS-CoV-2 associated fatalitySARS-CoV-2 associated mortalitySARS-CoV-2 deathSARS-CoV-2 epidemicSARS-CoV-2 fatalitySARS-CoV-2 global health crisisSARS-CoV-2 global pandemicSARS-CoV-2 induced deathSARS-CoV-2 induced fatalitySARS-CoV-2 induced mortalitySARS-CoV-2 infectionSARS-CoV-2 mortalitySARS-CoV-2 pandemicSARS-CoV-2 related deathSARS-CoV-2 related fatalitySARS-CoV-2 related mortalitySARS-CoV-2 spikeSARS-CoV-2 spike glycoproteinSARS-CoV-2 spike proteinSARS-CoV-2 therapeuticsSARS-CoV-2 therapySARS-CoV-2 treatmentSARS-CoV2SARS-CoV2 infectionSARS-associated corona virus 2SARS-associated coronavirus 2SARS-coronavirus-2SARS-coronavirus-2 epidemicSARS-coronavirus-2 pandemicSARS-coronavirus-2 therapeuticsSARS-related corona virus 2SARS-related coronavirus 2SARSCoV2SafetySepsisSevere 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 CoV 2 epidemicSevere Acute Respiratory Syndrome CoV 2 pandemicSevere 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 S proteinSevere acute respiratory syndrome coronavirus 2 epidemicSevere acute respiratory syndrome coronavirus 2 infectionSevere acute respiratory syndrome coronavirus 2 pandemicSevere acute respiratory syndrome coronavirus 2 spike glycoproteinSevere acute respiratory syndrome coronavirus 2 spike proteinSevere acute respiratory syndrome coronavirus 2 therapeuticsSevere acute respiratory syndrome related corona virus 2Shock LungSignal TransductionSignal Transduction SystemsSignalingSocial BehaviorSpecificityStiff lungSyrian HamstersSystemSystemic Capillary Leak SyndromeT cell growth factorT-Cell Growth FactorT-Cell Growth Factor ReceptorsT-Cell Stimulating FactorTCGF ReceptorsTestingTherapeuticThymocyte Stimulating FactorUnited States National Institutes of HealthViralViral ActivityViral DiseasesViral FunctionViral PhysiologyVirusVirus DiseasesWorkWuhan coronavirusangiotensin converting enzyme 2angiotensin converting enzyme IIantagonismantagonistanti-viral compoundanti-viral drugsanti-viral efficacyanti-viral medicationanti-viral therapeuticanti-viralsbiological signal transductionbound proteinclinical developmentcomputational methodologycomputational methodscomputer based methodcomputer methodscomputing methodcorona virus emergencecoronavirus disease 2019coronavirus disease 2019 S proteincoronavirus disease 2019 associated deathcoronavirus disease 2019 associated fatalitycoronavirus disease 2019 associated mortalitycoronavirus disease 2019 crisiscoronavirus disease 2019 deathcoronavirus disease 2019 epidemiccoronavirus disease 2019 fatalitycoronavirus disease 2019 global health crisiscoronavirus disease 2019 global pandemiccoronavirus disease 2019 health crisiscoronavirus disease 2019 induced deathcoronavirus disease 2019 induced fatalitycoronavirus disease 2019 induced mortalitycoronavirus disease 2019 infectioncoronavirus disease 2019 mortalitycoronavirus disease 2019 pandemiccoronavirus disease 2019 public health crisiscoronavirus disease 2019 related deathcoronavirus disease 2019 related fatalitycoronavirus disease 2019 related mortalitycoronavirus disease 2019 spike glycoproteincoronavirus disease 2019 spike proteincoronavirus disease 2019 therapeuticscoronavirus disease 2019 therapycoronavirus disease 2019 treatmentcoronavirus disease 2019 viruscoronavirus disease crisiscoronavirus disease epidemiccoronavirus disease pandemiccoronavirus disease-19coronavirus disease-19 global pandemiccoronavirus disease-19 mortalitycoronavirus disease-19 pandemiccoronavirus disease-19 viruscoronavirus emergencecoronavirus infectious disease-19costcytokinecytokine release syndromecytokine stormdeath due to COVID-19death due to COVID19death due to SARS-CoV-2death due to coronavirus disease 2019death due to severe acute respiratory syndrome coronavirus 2death in COVIDdeath in COVID-19death in SARS-CoV-2death in coronavirus diseasedeath in coronavirus disease 2019death in severe acute respiratory syndrome coronavirus 2designdesigningdetermine efficacydevelop a vaccinedevelop vaccinesdevelopment of a vaccinedevelopmentaldisabilitydrug/agenteconomic behavioreconomic impactefficacy analysisefficacy assessmentefficacy determinationefficacy evaluationefficacy examinationemergent CoVemergent corona virusemergent coronavirusemerging CoVemerging corona virusemerging coronavirusemerging pathogenevaluate efficacyexamine efficacyfatality due to COVID-19fatality due to COVID19fatality due to SARS-CoV-2fatality due to coronavirus disease 2019fatality due to severe acute respiratory syndrome coronavirus 2flu HAflu hemagglutininfuture pandemicgenetic protein engineeringhCoV19heavy metal Pbheavy metal leadhigh-end computingimmunogenicityimprovedin vivoinfected with COVID-19infected with COVID19infected with SARS-CoV-2infected with SARS-CoV2infected with coronavirus disease 2019infected with severe acute respiratory syndrome coronavirus 2influenza viral HAinfluenza viral hemagglutinininfluenza virus HAinfluenza virus hemagglutinininhibitorinnovateinnovationinnovativeinterferon beta 2mAbsmanufacturemimeticsmonoclonal Absmortality due to COVID-19mortality due to COVID19mortality due to SARS-CoV-2mortality due to coronavirus disease 2019mortality due to severe acute respiratory syndrome coronavirus 2nCoVnCoV2native protein drugnebulizationnebulizeneglectnew CoVnew corona virusnew coronavirusnew drug treatmentsnew drugsnew pathogennew pharmacological therapeuticnew therapeuticsnew therapynext generation therapeuticsnext pandemicnovelnovel CoVnovel corona virusnovel coronavirusnovel drug treatmentsnovel drugsnovel pathogennovel pharmaco-therapeuticnovel pharmacological therapeuticnovel therapeuticsnovel therapypandemicpandemic diseaseparallel computationparallel computerparallel computingpathogenpathogen genomepathogenomepharmaceutical proteinphase I protocolpre-clinical developmentpreclinical developmentprophylacticprotein designprotein drug agentprotein-based drugpublic health prioritiesrational designreceptorreceptor bindingreceptor boundsevere acute respiratory syndrome coronavirus 2 associated deathsevere acute respiratory syndrome coronavirus 2 associated fatalitysevere acute respiratory syndrome coronavirus 2 associated mortalitysevere acute respiratory syndrome coronavirus 2 deathsevere acute respiratory syndrome coronavirus 2 fatalitysevere acute respiratory syndrome coronavirus 2 global health crisissevere acute respiratory syndrome coronavirus 2 global pandemicsevere acute respiratory syndrome coronavirus 2 induced deathsevere acute respiratory syndrome coronavirus 2 induced fatalitysevere acute respiratory syndrome coronavirus 2 induced mortalitysevere acute respiratory syndrome coronavirus 2 mortalitysevere acute respiratory syndrome coronavirus 2 related deathsevere acute respiratory syndrome coronavirus 2 related fatalitysevere acute respiratory syndrome coronavirus 2 related mortalitysevere acute respiratory syndrome coronavirus 2 therapysevere acute respiratory syndrome coronavirus 2 treatmentsmall moleculesociobehaviorsociobehavioralspike proteins on SARS-CoV-2subcutaneoussubdermaltherapeutic proteintherapeutically effectivetherapeutics against COVID-19therapeutics against SARS-CoV-2therapeutics against SARS-coronavirus-2therapeutics against Severe acute respiratory syndrome coronavirus 2therapeutics against coronavirus disease 2019therapeutics for novel coronavirustreat COVID-19treat SARS-CoV-2treat coronavirus disease 2019treat severe acute respiratory syndrome coronavirus 2vaccine developmentviral infectionvirus infectionvirus-induced diseasewet lung
Full Description
PROJECT SUMMARY
One of the most pressing public health priorities for the COVID-19 pandemic is the development of an effective
and inexpensive therapeutic. The long-term goal of this proposal is to develop such COVID-19 treatments, as
well as the methods needed to rapidly create such molecules as soon as any new pathogen is identified. The
central hypothesis is that computational design can be used to quickly create proteins with potent antiviral activity
and others that suppress “cytokine storms” associated with advanced infection. Such countermeasures, if rapidly
developed and deployed, could save millions of lives during an outbreak until vaccines are developed. The
specific aims are to: 1) overcome current limitations in the discovery and development of protein therapeutics by
creating methods for the de novo design of hyper-stable miniproteins that bind tightly to vulnerable binding sites
on the SARS-CoV-2 Spike glycoprotein, including the receptor binding domain (RBD) of the ACE-2 cellular
receptor and the fusion peptide region; 2) Enhance the avidity of such anti-Spike minibinders through genetic
fusion of multiple copies, or through rational design of higher-order oligomers to create drug compounds that are
less prone to viral mutagenic escape; 3) Apply the same minibinder design pipeline to create cytokine receptor
antagonists of key cytokines IL-6 and IL-1β likely involved in acute respiratory distress syndrome (ADRS)
associated with COVID-19 mortality; 4) Assess the efficacy of antiviral and anti-interleukin minibinders by several
routes of delivery (intravenous, intranasal and subcutaneous) in rodent models of COVID-19 and assess
immunogenicity in order to identify those designs best suited for further preclinical development. As proof of
principle, the first anti-Spike minibinders have already been designed, were found to bind to SARS-CoV-2 Spike
RBD, and were found to neutralize live virus with activities rivaling the most potent known antibodies. This
proposal is innovative because it seeks to apply powerful emerging methods in the computational design of new
protein therapeutics to the COVID-19 pandemic. The proposal is significant because it would be the first example
of computational protein design yielding potent and entirely de novo antiviral and anti-inflammatory therapeutics
for an active pandemic. Ultimately, rapid minibinder design methods have the potential to generate treatments
for future pandemics, as well as for many other common and neglected diseases and conditions.
Grant Number: 5R01AI160052-05
NIH Institute/Center: NIH
Principal Investigator: DAVID BAKER
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