2024
Blocking Fas-signaling in adipocytes and hepatocytes prevents obesity-associated inflammation, insulin resistance, and hepatosteatosis
Bae S, Ullah I, Beloor J, Lim J, Chung K, Yi Y, Kang E, Yun G, Rhim T, Lee S. Blocking Fas-signaling in adipocytes and hepatocytes prevents obesity-associated inflammation, insulin resistance, and hepatosteatosis. Journal Of Industrial And Engineering Chemistry 2024, 135: 434-443. DOI: 10.1016/j.jiec.2024.01.055.Peer-Reviewed Original ResearchFas signalingObese mouse modelInhibit Fas signalingFas-mediated apoptosisObesity-associated inflammationFas-signalingInsulin resistanceAdipose tissueMouse modelHepatic steatosisMetabolic dysfunctionSystemic free fatty acidsPro-inflammatory cytokine secretionReduced apoptosisApoptosisFatty acidsReversible inflammationSystemic deliveryCytokine secretionLiver functionInflammatory pathwaysFree fatty acidsLiver steatosisInflammationHepatic triglycerideProof-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 formulationBlocking Fas signaling in adipose tissue ameliorates obesity-associated inflammation, insulin resistance, and hepatosteatosis
Beloor J, Ullah I, Kim J, Choi C, Kim S, Chung K, KR J, Yi Y, Rhim T, Kumar P, Lee S. Blocking Fas signaling in adipose tissue ameliorates obesity-associated inflammation, insulin resistance, and hepatosteatosis. Journal Of Pharmaceutical Investigation 2024, 54: 519-537. DOI: 10.1007/s40005-024-00668-9.Peer-Reviewed Original ResearchFas signalingMatrix-assisted laser desorption/ionization-time of flight spectrometryBlock Fas signalingNon-apoptotic signalsMatrix-assisted laser desorption/ionization-timeNon-apoptotic pathwaysAdipose tissue macrophagesHigh-fat diet-induced obese mouse modelImpaired insulin signalingInsulin resistanceDiet-induced obesity mouse modelDUTP nick end labeling assayRecruitment of adipose tissue macrophagesFas receptorInsulin signalingPeptide polymerizationNick end labeling assayTissue macrophagesAdipocyte apoptosisSuppress production of inflammatory cytokinesTerminal deoxynucleotidyl transferase dUTP nick end labeling assayReal-time PCRDeoxynucleotidyl transferase dUTP nick end labeling assayObese mouse modelGene expressionTargeted siRNA delivery to lung epithelia reduces airway inflammation in a mouse model of allergic asthma
Ullah I, Choi H, Choi C, Chung K, Jung J, Yun G, Heo S, Yi Y, Kang E, Kim S, Yoon H, Rhim T, Lee S. Targeted siRNA delivery to lung epithelia reduces airway inflammation in a mouse model of allergic asthma. Biotechnology And Bioprocess Engineering 2024, 29: 97-108. DOI: 10.1007/s12257-024-00027-3.Peer-Reviewed Original ResearchLung epithelial cellsEpithelial cellsAirway inflammationIL-4RAIL-13IL-4Mouse modelMouse model of allergic asthmaModel of allergic asthmaAllergic pulmonary inflammationCultured lung epithelial cellsReduce airway inflammationInterleukin (IL)-4Asthma mouse modelIL-4 receptorMulti-subunit receptorModel in vivoHypersecretion of mucusIL-4 signalingOvalbumin sensitizationTh2 cytokinesPulmonary inflammationAirway hyperresponsivenessAllergic asthmaLung epitheliaIntranasal Delivery of Anti-Apoptotic siRNA Complexed with Fas-Signaling Blocking Peptides Attenuates Cellular Apoptosis in Brain Ischemia
Chung K, Ullah I, Yi Y, Kang E, Yun G, Heo S, Kim M, Chung S, Park S, Lim J, Lee M, Rhim T, Lee S. Intranasal Delivery of Anti-Apoptotic siRNA Complexed with Fas-Signaling Blocking Peptides Attenuates Cellular Apoptosis in Brain Ischemia. Pharmaceutics 2024, 16: 290. PMID: 38399343, PMCID: PMC10892455, DOI: 10.3390/pharmaceutics16020290.Peer-Reviewed Original ResearchExtrinsic apoptosis pathwayIntrinsic apoptosis pathwayApoptosis pathwayNeuronal cell deathRelease of cytochrome c.Cell deathInhibit Fas signalingNona-arginine peptideFas-signalingFas signalingConfocal microscopy analysisMitochondria disruptionMiddle cerebral artery occlusionFas receptorIntrinsic pathwayTargeting BaxCytochrome c.Molecular mechanismsCellular apoptosisLigand signalingBaxBrain ischemiaPathwayTreatment of brain ischemiaSiRNA complexesIntranasal delivery of siRNA targeting NR2B attenuates cancer-associated neuropathic pain
Chung K, Ko H, Yi Y, Chung S, Lim J, Park S, Pyun S, Ullah I, Lee J, Kaang B, Lee S. Intranasal delivery of siRNA targeting NR2B attenuates cancer-associated neuropathic pain. Journal Of Pharmaceutical Investigation 2024, 54: 483-495. DOI: 10.1007/s40005-024-00667-w.Peer-Reviewed Original ResearchRo25-6981Pain signalsNR2B expressionMurine modelElectronic von Frey apparatusPhosphorylated extracellular signal-regulated kinaseMechanical withdrawal thresholdCancer-induced painLeft hind pawCancer-associated painCancer cell implantationEvaluate pain reductionBlock pain signalsAdministration of siRNAExtracellular signal-regulated kinaseSignal-regulated kinaseB16F10 melanoma cellsNeuropathic painPain modelWithdrawal thresholdPain reductionMelanoma modelIntranasal deliverySubunit NR2BC57BL/6 miceBioluminescence imaging reveals enhanced SARS-CoV-2 clearance in mice with combinatorial regimens
Ullah I, Escudie F, Scandale I, Gilani Z, Gendron-Lepage G, Gaudette F, Mowbray C, Fraisse L, Bazin R, Finzi A, Mothes W, Kumar P, Chatelain E, Uchil P. Bioluminescence imaging reveals enhanced SARS-CoV-2 clearance in mice with combinatorial regimens. IScience 2024, 27: 109049. PMID: 38361624, PMCID: PMC10867665, DOI: 10.1016/j.isci.2024.109049.Peer-Reviewed Original ResearchDirect-acting antiviralsEfficacy of direct-acting antiviralsVirus clearanceSARS-CoV-2Bioluminescence imagingSuppressed viral loadK18-hACE2 miceRapid virus clearanceNeutralizing antibody treatmentSARS-CoV-2 clearanceEvaluate therapeutic efficacyCOVID-19 convalescent plasmaMonotherapy regimensCombinatorial regimensAntibody treatmentViral loadSevere acute respiratory syndrome coronavirus 2Acute respiratory syndrome coronavirus 2Lung pathologyPandemic potentialRespiratory syndrome coronavirus 2Therapeutic arsenalConvalescent plasmaTreatment efficacySyndrome coronavirus 2Systemic 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 regionAdministrationSystemic Treatment with siRNA Targeting Gamma-Secretase Activating Protein Inhibits Amyloid-β Accumulation in Alzheimer’s Disease
Kim S, Ullah I, Beloor J, Chung K, Kim J, Yi Y, Kang E, Yun G, Heo S, Pyun S, Kim S, Kumar P, Lee S. Systemic Treatment with siRNA Targeting Gamma-Secretase Activating Protein Inhibits Amyloid-β Accumulation in Alzheimer’s Disease. Biomaterials Research 2024, 28: 0027. PMID: 38868092, PMCID: PMC11168191, DOI: 10.34133/bmr.0027.Peer-Reviewed Original Research
2023
Vaccinia Virus Strain MVA Expressing a Prefusion-Stabilized SARS-CoV-2 Spike Glycoprotein Induces Robust Protection and Prevents Brain Infection in Mouse and Hamster Models
Lorenzo M, Marín-López A, Chiem K, Jimenez-Cabello L, Ullah I, Utrilla-Trigo S, Calvo-Pinilla E, Lorenzo G, Moreno S, Ye C, Park J, Matía A, Brun A, Sánchez-Puig J, Nogales A, Mothes W, Uchil P, Kumar P, Ortego J, Fikrig E, Martinez-Sobrido L, Blasco R. Vaccinia Virus Strain MVA Expressing a Prefusion-Stabilized SARS-CoV-2 Spike Glycoprotein Induces Robust Protection and Prevents Brain Infection in Mouse and Hamster Models. Vaccines 2023, 11: 1006. PMID: 37243110, PMCID: PMC10220993, DOI: 10.3390/vaccines11051006.Peer-Reviewed Original ResearchVaccine candidatesStrong T cell responsesAngiotensin-converting enzyme 2Prime-boost regimensT cell responsesFull-length SARS-CoV-2 spike proteinEffective COVID-19 vaccineGolden Syrian hamstersSARS-CoV-2 spike glycoproteinSARS-CoV-2 spike proteinCOVID-19 vaccineRecombinant MVA vaccinesSARS-CoV-2S proteinBrain infectionMVA vaccinesCell-cell fusionAmino acid substitutionsVaccine platformHamster modelEnzyme 2Recombinant MVAVaccine vectorAnimal modelsRobust immunityTriple-negative breast cancer: epidemiology, molecular mechanisms, and modern vaccine-based treatment strategies
Karim A, Eun Kwon J, Ali T, Jang J, Ullah I, Lee Y, Park D, Park J, Jeang J, Kang S. Triple-negative breast cancer: epidemiology, molecular mechanisms, and modern vaccine-based treatment strategies. Biochemical Pharmacology 2023, 212: 115545. PMID: 37044296, DOI: 10.1016/j.bcp.2023.115545.Peer-Reviewed Original ResearchConceptsTriple-negative breast cancerGenome modificationBreast cancerDevelopmental signaling pathwaysCases of breast cancerGenome sequenceEstrogen receptor expressionBreast tumor subtypesOverexpression of HER2Unique mutational profileRecurring mutationsAbsence of progesteroneRare mutationsSusceptibility genesBRCA1/2 genesSignaling pathwayMolecular mechanismsGene amplificationReceptor expressionTumor subtypesPoor prognosisTumor heterogeneityMutation profilesTherapeutic strategiesGermline modification
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 activityProphylaxisIgGMolecular basis for antiviral activity of two pediatric neutralizing antibodies targeting SARS-CoV-2 Spike RBD
Chen Y, Prévost J, Ullah I, Romero H, Lisi V, Tolbert W, Grover J, Ding S, Gong S, Beaudoin-Bussières G, Gasser R, Benlarbi M, Vézina D, Anand S, Chatterjee D, Goyette G, Grunst M, Yang Z, Bo Y, Zhou F, Béland K, Bai X, Zeher A, Huang R, Nguyen D, Sherburn R, Wu D, Piszczek G, Paré B, Matthies D, Xia D, Richard J, Kumar P, Mothes W, Côté M, Uchil P, Lavallée V, Smith M, Pazgier M, Haddad E, Finzi A. Molecular basis for antiviral activity of two pediatric neutralizing antibodies targeting SARS-CoV-2 Spike RBD. IScience 2022, 26: 105783. PMID: 36514310, PMCID: PMC9733284, DOI: 10.1016/j.isci.2022.105783.Peer-Reviewed Original ResearchReceptor-binding domainSARS-CoV-2 patientsK18-hACE2 micePlasma neutralization activitySARS-CoV-2 variantsSARS-CoV-2 spike receptor-binding domainSpike receptor-binding domainProphylactic administrationNAb responsesPediatric patientsPotent NAbsLethal challengeNeutralizing antibodiesNeutralization activityDelta VOCEffector activityAntiviral mechanismAntiviral activityClinical interventionsPatientsNAbsAntibodiesEpitopesMolecular determinantsMolecular basisOP 6.2 – 00195 Targeted genome engineering of human t cells in vivo for HIV cure
Kumar P, Beloor J, Krishnaswamy J, Ullah I, Uchil P. OP 6.2 – 00195 Targeted genome engineering of human t cells in vivo for HIV cure. Journal Of Virus Eradication 2022, 8: 100247. DOI: 10.1016/j.jve.2022.100247.Peer-Reviewed Original ResearchComprehensive update on the monkeypox outbreak
Karim A, Kwon J, Karim M, Iftikhar H, Yasir M, Ullah I, Kang C. Comprehensive update on the monkeypox outbreak. Frontiers In Microbiology 2022, 13: 1037583. PMID: 36439787, PMCID: PMC9686369, DOI: 10.3389/fmicb.2022.1037583.Peer-Reviewed Original ResearchSARS-CoV-2Treatment of smallpoxSore throatMuscle achesSkin lesionsEndemic areasAntiviral drugsEndemic regionsPatterns of epidemicsSkin contactContact tracingMonkeypoxVaccineMonkeypox outbreakComprehensive updateOutbreakLack of informationTest capacityBody fluidsLymphadenopathyRashTecovirimatHeadacheFeverLesionsEngineered ACE2-Fc counters murine lethal SARS-CoV-2 infection through direct neutralization and Fc-effector activities
Chen Y, Sun L, Ullah I, Beaudoin-Bussières G, Anand SP, Hederman AP, Tolbert WD, Sherburn R, Nguyen DN, Marchitto L, Ding S, Wu D, Luo Y, Gottumukkala S, Moran S, Kumar P, Piszczek G, Mothes W, Ackerman ME, Finzi A, Uchil PD, Gonzalez FJ, Pazgier M. Engineered ACE2-Fc counters murine lethal SARS-CoV-2 infection through direct neutralization and Fc-effector activities. Science Advances 2022, 8: eabn4188. PMID: 35857504, PMCID: PMC9278865, DOI: 10.1126/sciadv.abn4188.Peer-Reviewed Original ResearchAngiotensin-converting enzyme 2Soluble angiotensin-converting enzyme 2Fc effector functionsSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptorLethal SARS-CoV-2 infectionK18-hACE2 mouse modelSARS-CoV-2 infectionAntibody-dependent cellular cytotoxicitySARS-CoV-2 antiviralsFc effector activityCoV-2 infectionSARS-CoV-2 variantsHalf maximal inhibitory concentrationComplement depositionACE2-FcCellular cytotoxicityEnzyme 2Mouse modelTherapeutic activityInhibitory concentrationTherapeutic settingDirect neutralizationInfectionReceptorsEffect of neutralizationVE607 stabilizes SARS-CoV-2 Spike in the “RBD-up” conformation and inhibits viral entry
Ding S, Ullah I, Gong SY, Grover J, Mohammadi M, Chen Y, Vézina D, Beaudoin-Bussières G, Verma VT, Goyette G, Gaudette F, Richard J, Yang D, Smith AB, Pazgier M, Côté M, Abrams C, Kumar P, Mothes W, Uchil P, Finzi A, Baron C. VE607 stabilizes SARS-CoV-2 Spike in the “RBD-up” conformation and inhibits viral entry. IScience 2022, 25: 104528. PMID: 35677392, PMCID: PMC9164512, DOI: 10.1016/j.isci.2022.104528.Peer-Reviewed Original ResearchSARS-CoV-2 infectionAuthentic SARS-CoV-2K18-hACE2 miceS-ACE2 interactionsDevelopment of immunotherapySARS-CoV-2 spikeSARS-CoV-2SARS-CoV-1Prophylactic treatmentLow micromolar concentrationsViral replicationACE2 receptorPseudoviral particlesViral entrySpike glycoproteinPotential targetCOVID-19Drug developmentInfectionACE2 interfaceHost cellsMicromolar concentrationsReceptorsTreatmentRBDA 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
Structural basis and mode of action for two broadly neutralizing antibodies against SARS-CoV-2 emerging variants of concern
Li W, Chen Y, Prévost J, Ullah I, Lu M, Gong SY, Tauzin A, Gasser R, Vézina D, Anand SP, Goyette G, Chaterjee D, Ding S, Tolbert WD, Grunst MW, Bo Y, Zhang S, Richard J, Zhou F, Huang RK, Esser L, Zeher A, Côté M, Kumar P, Sodroski J, Xia D, Uchil PD, Pazgier M, Finzi A, Mothes W. Structural basis and mode of action for two broadly neutralizing antibodies against SARS-CoV-2 emerging variants of concern. Cell Reports 2021, 38: 110210. PMID: 34971573, PMCID: PMC8673750, DOI: 10.1016/j.celrep.2021.110210.Peer-Reviewed Original ResearchVariants of concernProtective immune responseReceptor-binding domainImmune responseImmunogen designSevere acute respiratory syndrome coronavirus 2Acute respiratory syndrome coronavirus 2Respiratory syndrome coronavirus 2Syndrome coronavirus 2Mode of actionSARS-CoV-2 spikeSARS-CoV-2Vaccine immunogen designAntibody therapyCoronavirus 2Β-coronavirusMonoclonal antibodiesS1 subunitS2 subunitAntibodiesTherapyVariantsLive 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 neutralizationInfectionAntibodies