2024
Proof-of-concept studies with a computationally designed Mpro inhibitor as a synergistic combination regimen alternative to Paxlovid
Papini C, Ullah I, Ranjan A, Zhang S, Wu Q, Spasov K, Zhang C, Mothes W, Crawford J, Lindenbach B, Uchil P, Kumar P, Jorgensen W, Anderson K. Proof-of-concept studies with a computationally designed Mpro inhibitor as a synergistic combination regimen alternative to Paxlovid. Proceedings Of The National Academy Of Sciences Of The United States Of America 2024, 121: e2320713121. PMID: 38621119, PMCID: PMC11046628, DOI: 10.1073/pnas.2320713121.Peer-Reviewed Original ResearchConceptsDirect-acting antiviralsSARS-CoV-2Lack of off-target effectsIn vitro pharmacological profileTreatment of patientsDevelopment of severe symptomsPharmacological propertiesDrug-drug interactionsSARS-CoV-2 infectionProof-of-concept studySARS-CoV-2 M<sup>pro</sup>.Combination regimenImmunocompromised patientsLead compoundsSARS-CoV-2 main proteaseOral doseActive drugTreat infectionsPharmacological profileSARS-CoV-2 MPotential preclinical candidateOff-target effectsPatientsComplete recoveryCapsule formulationEye Drop with Fas-Blocking Peptide Attenuates Age-Related Macular Degeneration
Yi Y, Pyun S, Kim C, Yun G, Kang E, Heo S, Ullah I, Lee S. Eye Drop with Fas-Blocking Peptide Attenuates Age-Related Macular Degeneration. Cells 2024, 13: 548. PMID: 38534392, PMCID: PMC10969560, DOI: 10.3390/cells13060548.Peer-Reviewed Original ResearchConceptsAge-related macular degenerationDry age-related macular degenerationEye dropsMacular degenerationRetinal degenerationProgression of age-related macular degenerationRetinal degeneration mouse modelEye drop administrationRetinal degeneration modelRetinal cell deathExpression of inflammatory cytokinesLack of effective treatmentsRetinal thicknessAMD progressionIntravitreal administrationDrop administrationInflammatory cytokinesMouse modelEffective treatmentTranslational prospectsRabbit modelTherapeutic potentialFas-mediated apoptosisRetinal regionsSignificant health concernSystemic Treatment with Fas-Blocking Peptide Attenuates Apoptosis in Brain Ischemia
Chung S, Yi Y, Ullah I, Chung K, Park S, Lim J, Kim C, Pyun S, Kim M, Kim D, Lee M, Rhim T, Lee S. Systemic Treatment with Fas-Blocking Peptide Attenuates Apoptosis in Brain Ischemia. International Journal Of Molecular Sciences 2024, 25: 661. PMID: 38203830, PMCID: PMC10780202, DOI: 10.3390/ijms25010661.Peer-Reviewed Original ResearchConceptsBlood-brain barrierNeuronal cell deathCentral nervous systemBrain ischemiaIschemic strokeSystemic administrationLeptin receptor-deficient db/db miceDb/db miceLeptin peptideCerebral ischemic strokeCell deathInfarct volumeNeuronal injurySystemic treatmentDb miceBBB penetrationIschemic regionNervous systemNeurological disordersTherapeutic potentialSystemic deliveryIschemiaTherapeutic drugsInfarction regionAdministration
2022
The Fc-effector function of COVID-19 convalescent plasma contributes to SARS-CoV-2 treatment efficacy in mice
Ullah I, Beaudoin-Bussières G, Symmes K, Cloutier M, Ducas E, Tauzin A, Laumaea A, Grunst M, Dionne K, Richard J, Bégin P, Mothes W, Kumar P, Bazin R, Finzi A, Uchil P. The Fc-effector function of COVID-19 convalescent plasma contributes to SARS-CoV-2 treatment efficacy in mice. Cell Reports Medicine 2022, 4: 100893. PMID: 36584683, PMCID: PMC9799175, DOI: 10.1016/j.xcrm.2022.100893.Peer-Reviewed Original ResearchConceptsCOVID-19 convalescent plasmaFc effector functionsSARS-CoV-2 controlFc effector activityInnate immune cellsCCP efficacyHACE2 miceConvalescent plasmaImmunoglobulin levelsPlasma therapyImmune cellsTreatment efficacyDelays mortalityIgG fractionFc functionLow neutralizingTherapySecond lineMortalityMicePlasma contributesEfficacyFC activityProphylaxisIgGA Fc-enhanced NTD-binding non-neutralizing antibody delays virus spread and synergizes with a nAb to protect mice from lethal SARS-CoV-2 infection
Beaudoin-Bussières G, Chen Y, Ullah I, Prévost J, Tolbert WD, Symmes K, Ding S, Benlarbi M, Gong SY, Tauzin A, Gasser R, Chatterjee D, Vézina D, Goyette G, Richard J, Zhou F, Stamatatos L, McGuire AT, Charest H, Roger M, Pozharski E, Kumar P, Mothes W, Uchil PD, Pazgier M, Finzi A. A Fc-enhanced NTD-binding non-neutralizing antibody delays virus spread and synergizes with a nAb to protect mice from lethal SARS-CoV-2 infection. Cell Reports 2022, 38: 110368. PMID: 35123652, PMCID: PMC8786652, DOI: 10.1016/j.celrep.2022.110368.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, NeutralizingAntibodies, ViralAntibody-Dependent Cell CytotoxicityCOVID-19COVID-19 SerotherapyDisease Models, AnimalEpitopesHumansImmunization, PassiveImmunoglobulin Fab FragmentsImmunoglobulin Fc FragmentsMiceProtein BindingProtein ConformationSARS-CoV-2Spike Glycoprotein, Coronavirus
2021
Live imaging of SARS-CoV-2 infection in mice reveals that neutralizing antibodies require Fc function for optimal efficacy
Ullah I, Prévost J, Ladinsky MS, Stone H, Lu M, Anand SP, Beaudoin-Bussières G, Symmes K, Benlarbi M, Ding S, Gasser R, Fink C, Chen Y, Tauzin A, Goyette G, Bourassa C, Medjahed H, Mack M, Chung K, Wilen CB, Dekaban GA, Dikeakos JD, Bruce EA, Kaufmann DE, Stamatatos L, McGuire AT, Richard J, Pazgier M, Bjorkman PJ, Mothes W, Finzi A, Kumar P, Uchil PD. Live imaging of SARS-CoV-2 infection in mice reveals that neutralizing antibodies require Fc function for optimal efficacy. Immunity 2021, 54: 2143-2158.e15. PMID: 34453881, PMCID: PMC8372518, DOI: 10.1016/j.immuni.2021.08.015.Peer-Reviewed Original ResearchConceptsCOVID-19 convalescent subjectsSARS-CoV-2 infectionBioluminescence imagingK18-hACE2 miceLive bioluminescence imagingNatural killer cellsFc effector functionsSARS-CoV-2Convalescent subjectsKiller cellsPotent NAbsImmune protectionInflammatory responseEffector functionsNasal cavityNaB treatmentOptimal efficacyFc functionDepletion studiesMiceNAbsCOVID-19Direct neutralizationInfectionAntibodiesIn vivo imaging of retrovirus infection reveals a role for Siglec-1/CD169 in multiple routes of transmission
Haugh KA, Ladinsky MS, Ullah I, Stone HM, Pi R, Gilardet A, Grunst MW, Kumar P, Bjorkman PJ, Mothes W, Uchil PD. In vivo imaging of retrovirus infection reveals a role for Siglec-1/CD169 in multiple routes of transmission. ELife 2021, 10: e64179. PMID: 34223819, PMCID: PMC8298093, DOI: 10.7554/elife.64179.Peer-Reviewed Original ResearchConceptsSentinel macrophagesSiglec-1/CD169Immune surveillance functionCommon host factorMesenteric sacsPeyer's patchesGastrointestinal tractOral routeReporter virusRetrovirus transmissionRetrovirus infectionFrontline cellsRetroviral pathogenesisHost factorsBioluminescence imagingVirus entryIncoming virusInfectionRetrovirus life cycleCD169Early eventsMacrophagesMultiscale imaging approachVirusSurveillance functionModulating HIV-1 envelope glycoprotein conformation to decrease the HIV-1 reservoir
Rajashekar JK, Richard J, Beloor J, Prévost J, Anand SP, Beaudoin-Bussières G, Shan L, Herndler-Brandstetter D, Gendron-Lepage G, Medjahed H, Bourassa C, Gaudette F, Ullah I, Symmes K, Peric A, Lindemuth E, Bibollet-Ruche F, Park J, Chen HC, Kaufmann DE, Hahn BH, Sodroski J, Pazgier M, Flavell RA, Smith AB, Finzi A, Kumar P. Modulating HIV-1 envelope glycoprotein conformation to decrease the HIV-1 reservoir. Cell Host & Microbe 2021, 29: 904-916.e6. PMID: 34019804, PMCID: PMC8214472, DOI: 10.1016/j.chom.2021.04.014.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, NeutralizingAntibody-Dependent Cell CytotoxicityAntiviral AgentsCD4 AntigensCD4-Positive T-LymphocytesCell LineEnv Gene Products, Human Immunodeficiency VirusEpitopesFemaleGlycoproteinsHEK293 CellsHIV InfectionsHIV-1HumansImmunoglobulin Fc FragmentsKiller Cells, NaturalMaleMiceMice, SCIDModels, AnimalProtein ConformationVirus ReplicationConceptsAntibody-dependent cellular cytotoxicityHIV-1 reservoirFc effector functionsViral reboundHumanized miceHIV-1HIV-1-infected individualsHIV-1-infected cellsAutologous HIV-1Natural killer cellsCD4-mimetic compoundsHIV-1 replicationSmall CD4-mimetic compoundsART interruptionFunctional cureNK cellsKiller cellsCellular cytotoxicityTherapeutic utilityInfected individualsCD4mcVirus reservoirMiceViral envelopeAntibody recognition
2020
Targeted Delivery of Recombinant Heat Shock Protein 27 to Cardiomyocytes Promotes Recovery from Myocardial Infarction
Kim N, Ullah I, Chung K, Lee D, Cha MJ, Ban H, Choi CS, Kim S, Hwang KC, Kumar P, Lee SK. Targeted Delivery of Recombinant Heat Shock Protein 27 to Cardiomyocytes Promotes Recovery from Myocardial Infarction. Molecular Pharmaceutics 2020, 17: 2034-2043. PMID: 32364395, DOI: 10.1021/acs.molpharmaceut.0c00192.Peer-Reviewed Original ResearchConceptsAT1 receptor antibodyIschemic heart diseaseIschemia/reperfusionMyocardial infarctionMI ratsReceptor antibodiesHeart diseaseAngiotensin II type 1 receptorII type 1 receptorType 1 receptorAreas of fibrosisHeat shock protein 27Cause of deathRat MI modelShock protein 27Hypoxia-induced apoptosisIschemic injuryTherapeutic optionsCardiac functionProtective effectPromotes recoveryCardiomyocyte deathNormal responseMI modelSystemic deliveryNose-to-Brain Delivery of Cancer-Targeting Paclitaxel-Loaded Nanoparticles Potentiates Antitumor Effects in Malignant Glioblastoma
Ullah I, Chung K, Bae S, Li Y, Kim C, Choi B, Nam HY, Kim SH, Yun CO, Lee KY, Kumar P, Lee SK. Nose-to-Brain Delivery of Cancer-Targeting Paclitaxel-Loaded Nanoparticles Potentiates Antitumor Effects in Malignant Glioblastoma. Molecular Pharmaceutics 2020, 17: 1193-1204. PMID: 31944768, DOI: 10.1021/acs.molpharmaceut.9b01215.Peer-Reviewed Original ResearchConceptsGlioblastoma multiformeBrain deliveryPoor drug distributionNormal brain cellsCancer cell proliferationCurative treatmentTumor burdenIntranasal inoculationTumor recurrenceAggressive tumorsEnhanced anticancer effectTumor regrowthTherapeutic evidenceTumor remnantsGBM therapyAntitumor effectsBrain cellsTherapeutic efficacyMalignant glioblastomaAnticancer effectsCell proliferationCancer-specific deliveryDrug distributionChemotherapyPaclitaxel
2018
Small Interfering RNA-Mediated Control of Virus Replication in the CNS Is Therapeutic and Enables Natural Immunity to West Nile Virus
Beloor J, Maes N, Ullah I, Uchil P, Jackson A, Fikrig E, Lee SK, Kumar P. Small Interfering RNA-Mediated Control of Virus Replication in the CNS Is Therapeutic and Enables Natural Immunity to West Nile Virus. Cell Host & Microbe 2018, 23: 549-556.e3. PMID: 29606496, PMCID: PMC6074029, DOI: 10.1016/j.chom.2018.03.001.Peer-Reviewed Original ResearchConceptsWest Nile virusWNV infectionCell-mediated immune responsesLate-stage therapySubsequent WNV infectionWNV-infected miceLong-term immunityNile virusWNV E proteinViral burdenIntranasal routeVirus clearanceVirus infectionImmune responseMice succumbPeripheral tissuesNatural immunitySurvival rateDisease resultsDay 9Virus replicationInfectionImmunityCNSVirus
2016
Trileucine residues in a ligand-CPP-based siRNA delivery platform improve endosomal escape of siRNA
Ullah I, Chung K, Beloor J, Kim J, Cho M, Kim N, Lee KY, Kumar P, Lee SK. Trileucine residues in a ligand-CPP-based siRNA delivery platform improve endosomal escape of siRNA. Journal Of Drug Targeting 2016, 25: 320-329. PMID: 27820977, DOI: 10.1080/1061186x.2016.1258566.Peer-Reviewed Original Research