Assaf Alon, PhD
Assistant Professor of PharmacologyCards
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Featured Publications
The dynamic disulphide relay of quiescin sulphydryl oxidase
Alon A, Grossman I, Gat Y, Kodali V, DiMaio F, Mehlman T, Haran G, Baker D, Thorpe C, Fass D. The dynamic disulphide relay of quiescin sulphydryl oxidase. Nature 2012, 488: 414-418. PMID: 22801504, PMCID: PMC3521037, DOI: 10.1038/nature11267.Peer-Reviewed Original ResearchIdentification of the gene that codes for the σ2 receptor
Alon A, Schmidt H, Wood M, Sahn J, Martin S, Kruse A. Identification of the gene that codes for the σ2 receptor. Proceedings Of The National Academy Of Sciences Of The United States Of America 2017, 114: 7160-7165. PMID: 28559337, PMCID: PMC5502638, DOI: 10.1073/pnas.1705154114.Peer-Reviewed Original ResearchMeSH KeywordsAlzheimer DiseaseAnimalsAspartic AcidCarrier ProteinsCattleCholesterolEndoplasmic ReticulumGene Expression RegulationHumansInsectaIntracellular Signaling Peptides and ProteinsLigandsLiverMCF-7 CellsMembrane GlycoproteinsMembrane ProteinsNiemann-Pick C1 ProteinPC12 CellsProtein BindingRatsReceptors, sigmaRecombinant ProteinsRNA, Small InterferingSchizophreniaConceptsEndoplasmic reticulum-resident transmembrane proteinChemical biology approachPotential drug targetsTransmembrane proteinsMolecular cloningBiology approachLigand recognitionDrug targetsGenesBiological methodsTMEM97Therapeutic targetProteinMedical interestReceptorsAsp56NPC1ClonesS2 receptorsMolecular propertiesNeurological disordersSterolsTargetStructures of the σ2 receptor enable docking for bioactive ligand discovery
Alon A, Lyu J, Braz J, Tummino T, Craik V, O’Meara M, Webb C, Radchenko D, Moroz Y, Huang X, Liu Y, Roth B, Irwin J, Basbaum A, Shoichet B, Kruse A. Structures of the σ2 receptor enable docking for bioactive ligand discovery. Nature 2021, 600: 759-764. PMID: 34880501, PMCID: PMC8867396, DOI: 10.1038/s41586-021-04175-x.Peer-Reviewed Original ResearchConceptsCrystal structureStructure-based screeningBioactive ligand discoveryDocking posesDocking screeningLigand discoveryDocking scoreVirtual moleculesS2 receptorsLigandLarge librariesDockingCrystalMouse model of neuropathic painModel of neuropathic painStructureMechanical hypersensitivityNeuropathic painAffinityS1 receptorsMouse modelCompoundsMoleculesReceptorsChemotypes
2024
Antagonistic nanobodies implicate mechanism of GSDMD pore formation and potential therapeutic application
Schiffelers L, Tesfamariam Y, Jenster L, Diehl S, Binder S, Normann S, Mayr J, Pritzl S, Hagelauer E, Kopp A, Alon A, Geyer M, Ploegh H, Schmidt F. Antagonistic nanobodies implicate mechanism of GSDMD pore formation and potential therapeutic application. Nature Communications 2024, 15: 8266. PMID: 39327452, PMCID: PMC11427689, DOI: 10.1038/s41467-024-52110-1.Peer-Reviewed Original ResearchConceptsMembrane insertionGasdermin DN-terminal domainCleavage of gasdermin DPore formationPro-inflammatory caspasesPyroptosis to apoptosisActivated caspase-3Caspase-1 activationTarget membraneCaspase-3Assembled poresPlasma membraneCytosolic expressionLiving cellsConformational changesEnhanced caspase-1 activityOligomerizationPotential therapeutic applicationsInflammasome activationNanobodiesPyroptosisStudy pore formationMembraneTherapeutic applicationsAlphaFold2 structures guide prospective ligand discovery
Lyu J, Kapolka N, Gumpper R, Alon A, Wang L, Jain M, Barros-Álvarez X, Sakamoto K, Kim Y, DiBerto J, Kim K, Glenn I, Tummino T, Huang S, Irwin J, Tarkhanova O, Moroz Y, Skiniotis G, Kruse A, Shoichet B, Roth B. AlphaFold2 structures guide prospective ligand discovery. Science 2024, 384: eadn6354. PMID: 38753765, PMCID: PMC11253030, DOI: 10.1126/science.adn6354.Peer-Reviewed Original ResearchConceptsExperimental structuresLigand discoveryStructure-based drug designAlphaFold2 structuresAlphaFold2 modelsSample conformationsResidue conformationsDrug designLarge librariesDockingLigand recognitionLigandConformationLow energyStructureHit rateMoleculesAlphaFold2 predictionsTesting hundredsCryo-electron microscopy structureAlphaFold2Cryo-electronHitsCompare resultsEnergy
2022
The SpoVA membrane complex is required for dipicolinic acid import during sporulation and export during germination
Gao Y, Barajas-Ornelas R, Amon J, Ramírez-Guadiana F, Alon A, Brock K, Marks D, Kruse A, Rudner D. The SpoVA membrane complex is required for dipicolinic acid import during sporulation and export during germination. Genes & Development 2022, 36: 634-646. PMID: 35654455, PMCID: PMC9186386, DOI: 10.1101/gad.349488.122.Peer-Reviewed Original ResearchConceptsMembrane complexStress-resistant sporesEndospore-forming bacteriaResponse to starvationDipicolinic acidEB subunitsDPA releaseCytoplasmic plugIn vivo analysisMembrane channelsStress resistanceD subunitDormant sporesMolecular basisResume growthSporulationNutrient detectionSporesGerminationProteinOperonSpoVAMutagenesisLociMembrane
2021
The Spliced Leader RNA Silencing (SLS) Pathway in Trypanosoma brucei Is Induced by Perturbations of Endoplasmic Reticulum, Golgi Complex, or Mitochondrial Protein Factors: Functional Analysis of SLS-Inducing Kinase PK3
Okalang U, Bar-Ner B, Rajan K, Friedman N, Aryal S, Egarmina K, Hope R, Khazanov N, Senderowitz H, Alon A, Fass D, Michaeli S. The Spliced Leader RNA Silencing (SLS) Pathway in Trypanosoma brucei Is Induced by Perturbations of Endoplasmic Reticulum, Golgi Complex, or Mitochondrial Protein Factors: Functional Analysis of SLS-Inducing Kinase PK3. MBio 2021, 12: e02602-21. PMID: 34844425, PMCID: PMC8630539, DOI: 10.1128/mbio.02602-21.Peer-Reviewed Original ResearchConceptsSpliced leader RNA silencingER oxidoreductin 1Quiescin sulfhydryl oxidaseER-resident chaperone BiPMitochondrial protein importEndoplasmic reticulumProtein importChaperone BiPRNA silencingSpliced leader (SL) RNACausative agent of human African sleeping sicknessSulfhydryl oxidasePerturbation of endoplasmic reticulumSL RNA transcriptionInduction of programmed cell deathHuman African sleeping sicknessATP-binding domainPotential novel drug targetsParasite Trypanosoma bruceiSerine-threonine kinaseNovel drug targetsProtein sortingAfrican sleeping sicknessProtein translocationPhosphorylation eventsDormant spores sense amino acids through the B subunits of their germination receptors
Artzi L, Alon A, Brock K, Green A, Tam A, Ramírez-Guadiana F, Marks D, Kruse A, Rudner D. Dormant spores sense amino acids through the B subunits of their germination receptors. Nature Communications 2021, 12: 6842. PMID: 34824238, PMCID: PMC8617281, DOI: 10.1038/s41467-021-27235-2.Peer-Reviewed Original ResearchConceptsAmino acid-polyamine-organocation superfamilyEvolutionary co-variation analysisL-alanine recognitionB subunitStress-resistant sporesSuperfamily of transportersPutative membrane receptorL-alanineResponse to L-alanineGerABNutrient sensingBacillus subtilisGerminant receptorsBulky residuesAmino acidsMembrane receptorsPrototypic receptorNutrient detectionSporesGerminationCo-variance analysisL-serineMutationsL-leucineBacillalesDrug-induced phospholipidosis confounds drug repurposing for SARS-CoV-2
Tummino T, Rezelj V, Fischer B, Fischer A, O'Meara M, Monel B, Vallet T, White K, Zhang Z, Alon A, Schadt H, O'Donnell H, Lyu J, Rosales R, McGovern B, Rathnasinghe R, Jangra S, Schotsaert M, Galarneau J, Krogan N, Urban L, Shokat K, Kruse A, García-Sastre A, Schwartz O, Moretti F, Vignuzzi M, Pognan F, Shoichet B. Drug-induced phospholipidosis confounds drug repurposing for SARS-CoV-2. Science 2021, 373: 541-547. PMID: 34326236, PMCID: PMC8501941, DOI: 10.1126/science.abi4708.Peer-Reviewed Original ResearchConceptsEarly drug discoveryPhysicochemical properties of drugsDrug discoveryInduce phospholipidosisCationic amphiphilic drugsSigma receptor ligandsPhysicochemical propertiesProperties of drugsAmphiphilic drugsSARS-CoV-2PhospholipidosisReceptor ligandsRepurposed drugsLigandSevere acute respiratory syndrome coronavirus 2Acute respiratory syndrome coronavirus 2MoleculesAntiviral activityAntiviral efficacyClinical trialsRespiratory syndrome coronavirus 2COVID-19: Famotidine, Histamine, Mast Cells, and Mechanisms
Malone R, Tisdall P, Fremont-Smith P, Liu Y, Huang X, White K, Miorin L, Moreno E, Alon A, Delaforge E, Hennecker C, Wang G, Pottel J, Blair R, Roy C, Smith N, Hall J, Tomera K, Shapiro G, Mittermaier A, Kruse A, García-Sastre A, Roth B, Glasspool-Malone J, Ricke D. COVID-19: Famotidine, Histamine, Mast Cells, and Mechanisms. Frontiers In Pharmacology 2021, 12: 633680. PMID: 33833683, PMCID: PMC8021898, DOI: 10.3389/fphar.2021.633680.Peer-Reviewed Original ResearchSARS-CoV-2 infectionCOVID-19 diseaseSARS-CoV-2Mast cell activationClinical COVID-19Acute viral diseaseMechanism of actionSymptoms of COVID-19Dose selectionClinical dataTreatment strategiesTreatment of COVID-19 diseaseHistamine releaseCell activationWell-characterized drugsCOVID-19 symptomsClinical COVID-19 diseaseOral formFamotidineMedical countermeasuresDiseaseInpatient treatmentCOVID-19InfectionSymptoms
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