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 formulation
2022
Engineered 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
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 neutralizationInfectionAntibodies