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
2023
PLSCR1 is a cell-autonomous defence factor against SARS-CoV-2 infection
Xu D, Jiang W, Wu L, Gaudet R, Park E, Su M, Cheppali S, Cheemarla N, Kumar P, Uchil P, Grover J, Foxman E, Brown C, Stansfeld P, Bewersdorf J, Mothes W, Karatekin E, Wilen C, MacMicking J. PLSCR1 is a cell-autonomous defence factor against SARS-CoV-2 infection. Nature 2023, 619: 819-827. PMID: 37438530, PMCID: PMC10371867, DOI: 10.1038/s41586-023-06322-y.Peer-Reviewed Original ResearchConceptsC-terminal β-barrel domainSpike-mediated fusionCell-autonomous defenseLarge-scale exome sequencingΒ-barrel domainGenome-wide CRISPRSARS-CoV-2 infectionHost cell cytosolScramblase activityPhospholipid scramblaseLive SARS-CoV-2 infectionHuman lung epitheliumPLSCR1SARS-CoV-2 USASingle-molecule switchingSARS-CoV-2 variantsExome sequencingHuman populationRestriction factorsViral RNANew SARS-CoV-2 variantsSARS-CoV-2Robust activityLung epitheliumDefense factors
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 activityProphylaxisIgG
2019
In vivo Imaging-Driven Approaches to Study Virus Dissemination and Pathogenesis
Uchil PD, Haugh KA, Pi R, Mothes W. In vivo Imaging-Driven Approaches to Study Virus Dissemination and Pathogenesis. Annual Review Of Virology 2019, 6: 1-24. PMID: 31283440, PMCID: PMC7217087, DOI: 10.1146/annurev-virology-101416-041429.Peer-Reviewed Original ResearchAssociating HIV-1 envelope glycoprotein structures with states on the virus observed by smFRET
Lu M, Ma X, Castillo-Menendez LR, Gorman J, Alsahafi N, Ermel U, Terry DS, Chambers M, Peng D, Zhang B, Zhou T, Reichard N, Wang K, Grover JR, Carman BP, Gardner MR, Nikić-Spiegel I, Sugawara A, Arthos J, Lemke EA, Smith AB, Farzan M, Abrams C, Munro JB, McDermott AB, Finzi A, Kwong PD, Blanchard SC, Sodroski JG, Mothes W. Associating HIV-1 envelope glycoprotein structures with states on the virus observed by smFRET. Nature 2019, 568: 415-419. PMID: 30971821, PMCID: PMC6655592, DOI: 10.1038/s41586-019-1101-y.Peer-Reviewed Original ResearchConceptsSingle-molecule fluorescence resonance energy transferCryo-electron microscopy studiesHigh-resolution structuresFluorescence resonance energy transferState 1 conformationProline substitutionConformational statesResonance energy transferDisulfide bondsCell entryIntermediate conformationsReceptor moleculesGlycoprotein structureStructural studiesIntact virionsViral EnvCD4 receptor moleculeIntact virusConformationState 2TrimerState 1
2018
A Protective Role for the Lectin CD169/Siglec-1 against a Pathogenic Murine Retrovirus
Uchil PD, Pi R, Haugh KA, Ladinsky MS, Ventura JD, Barrett BS, Santiago ML, Bjorkman PJ, Kassiotis G, Sewald X, Mothes W. A Protective Role for the Lectin CD169/Siglec-1 against a Pathogenic Murine Retrovirus. Cell Host & Microbe 2018, 25: 87-100.e10. PMID: 30595553, PMCID: PMC6331384, DOI: 10.1016/j.chom.2018.11.011.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCD8-Positive T-LymphocytesCell ProliferationDendritic CellsDisease Models, AnimalErythroblastsFemaleInterferon Type ILectinsLymph NodesMacrophagesMaleMiceMice, Inbred BALB CMice, Inbred C57BLProtective AgentsRetroviridaeRetroviridae InfectionsSialic Acid Binding Ig-like Lectin 1SpleenT-Lymphocytes, CytotoxicViral LoadConceptsCD169/SiglecEffective cytotoxic T lymphocyte (CTL) responseProtective roleCytotoxic T lymphocyte responsesLymph node infectionT lymphocyte responsesHigh viral loadSusceptible mouse strainsMarginal zone metallophilic macrophagesPermissive lymphocytesCytotoxic CD8Lymphocyte responsesViral loadSubcapsular sinusComplex infectionMurine modelViral disseminationMetallophilic macrophagesRed pulpCell responsesSystemic spreadMouse strainsPathogenesisCells 1CD169
2015
Retroviruses use CD169-mediated trans-infection of permissive lymphocytes to establish infection
Sewald X, Ladinsky MS, Uchil PD, Beloor J, Pi R, Herrmann C, Motamedi N, Murooka TT, Brehm MA, Greiner DL, Shultz LD, Mempel TR, Bjorkman PJ, Kumar P, Mothes W. Retroviruses use CD169-mediated trans-infection of permissive lymphocytes to establish infection. Science 2015, 350: 563-567. PMID: 26429886, PMCID: PMC4651917, DOI: 10.1126/science.aab2749.Peer-Reviewed Original ResearchConceptsHuman immunodeficiency virusLymph nodesMurine leukemia virusCD169/SiglecSecondary lymphoid tissuesPermissive lymphocytesDendritic cellsImmunodeficiency virusSynaptic contactsLymphoid tissueRobust infectionVirological synapsesI-type lectinsRetroviral spreadViral spreadUninfected cellsInfectionLeukemia virusVirusMacrophagesCellsRetrovirusesCell-cell contactCD169Lymphocytes
2000
The Sec61p Complex Mediates the Integration of a Membrane Protein by Allowing Lipid Partitioning of the Transmembrane Domain
Heinrich S, Mothes W, Brunner J, Rapoport T. The Sec61p Complex Mediates the Integration of a Membrane Protein by Allowing Lipid Partitioning of the Transmembrane Domain. Cell 2000, 102: 233-244. PMID: 10943843, DOI: 10.1016/s0092-8674(00)00028-3.Peer-Reviewed Original ResearchSecreted cathepsin L generates endostatin from collagen XVIII
Felbor U, Dreier L, Bryant R, Ploegh H, Olsen B, Mothes W. Secreted cathepsin L generates endostatin from collagen XVIII. The EMBO Journal 2000, 19: 1187-1194. PMID: 10716919, PMCID: PMC305660, DOI: 10.1093/emboj/19.6.1187.Peer-Reviewed Original ResearchAnimalsCathepsin LCathepsinsCell LineCollagenCollagen Type XVIIICulture Media, ConditionedCysteine EndopeptidasesEndopeptidasesEndostatinsEndothelium, VascularEnzyme PrecursorsHumansHydrogen-Ion ConcentrationKineticsMatrix MetalloproteinasesMiceModels, BiologicalMolecular WeightPeptide FragmentsProtein Processing, Post-TranslationalProtein Structure, TertiaryRecombinant Fusion ProteinsTumor Cells, Cultured
1998
Signal Sequence Recognition in Cotranslational Translocation by Protein Components of the Endoplasmic Reticulum Membrane
Mothes W, Jungnickel B, Brunner J, Rapoport T. Signal Sequence Recognition in Cotranslational Translocation by Protein Components of the Endoplasmic Reticulum Membrane. Journal Of Cell Biology 1998, 142: 355-364. PMID: 9679136, PMCID: PMC2133054, DOI: 10.1083/jcb.142.2.355.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBinding SitesBiological Transport, ActiveCross-Linking ReagentsDetergentsDogsEndoplasmic ReticulumFungal ProteinsIn Vitro TechniquesIntracellular MembranesMembrane LipidsMembrane ProteinsProlactinProtein BiosynthesisProtein PrecursorsRibosomesSaccharomyces cerevisiae ProteinsSEC Translocation ChannelsSignal Recognition ParticleSolutionsConceptsEndoplasmic reticulum membraneSignal sequenceProtein componentsReticulum membraneSignal sequence recognitionSequence recognitionProtein-protein interactionsPhotocross-linking experimentsTranslocation channelCotranslational insertionTranslocation componentsCotranslational translocationMembrane proteinsSecretory proteinsNative membranesBinding sitesBulk lipidsSpecific binding sitesProteinDetergent solutionSequenceLipidsMembraneTranslocationSites
1997
Molecular Mechanism of Membrane Protein Integration into the Endoplasmic Reticulum
Mothes W, Heinrich S, Graf R, Nilsson I, von Heijne G, Brunner J, Rapoport T. Molecular Mechanism of Membrane Protein Integration into the Endoplasmic Reticulum. Cell 1997, 89: 523-533. PMID: 9160744, DOI: 10.1016/s0092-8674(00)80234-2.Peer-Reviewed Original ResearchConceptsTranslocation channelCytosolic domainTransmembrane sequenceMembrane proteinsMolecular mechanismsEndoplasmic reticulumHydrophobic transmembrane sequenceMembrane protein integrationHydrophilic polypeptide segmentsProtein integrationLipid environmentPolypeptide segmentsProteinReticulumLipid phaseSequenceMembraneRibosomesCytosolFoldingDomainMechanismAssemblySignificant implicationsTranslation