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
A High-Throughput, High-Containment Human Primary Epithelial Airway Organ-on-Chip Platform for SARS-CoV-2 Therapeutic Screening
Fisher C, Medie F, Luu R, Gaibler R, Mulhern T, Miller C, Zhang C, Rubio L, Marr E, Vijayakumar V, Gabriel E, Quezada L, Zhang C, Anderson K, Jorgensen W, Alladina J, Medoff B, Borenstein J, Gard A. A High-Throughput, High-Containment Human Primary Epithelial Airway Organ-on-Chip Platform for SARS-CoV-2 Therapeutic Screening. Cells 2023, 12: 2639. PMID: 37998374, PMCID: PMC10669988, DOI: 10.3390/cells12222639.Peer-Reviewed Original ResearchConceptsChip platformHigh-throughput organSARS-CoV-2 infectionHigh throughputScreening applicationsDisease modelingEfficacy of remdesivirNative virusRobust viral replicationSARS-CoV-2Therapeutic screeningPlatformRapid developmentAntiviral effectLung tissuePreclinical modelsEfficacious vaccineHuman donorsViral replicationEffective therapeuticsPlaque assayAntiviral studiesWorldwide pandemicThroughputRT-qPCR
2017
Covalent inhibitors for eradication of drug-resistant HIV-1 reverse transcriptase: From design to protein crystallography
Chan AH, Lee WG, Spasov KA, Cisneros JA, Kudalkar SN, Petrova ZO, Buckingham AB, Anderson KS, Jorgensen WL. Covalent inhibitors for eradication of drug-resistant HIV-1 reverse transcriptase: From design to protein crystallography. Proceedings Of The National Academy Of Sciences Of The United States Of America 2017, 114: 9725-9730. PMID: 28827354, PMCID: PMC5594698, DOI: 10.1073/pnas.1711463114.Peer-Reviewed Original ResearchConceptsHIV-1 reverse transcriptaseNonnucleoside RT inhibitorsDrug-resistant HIV-1 reverse transcriptaseReverse transcriptaseHIV-1 infectionTreatment of HIVT cell assaysDevelopment of resistanceRT inhibitorsAntiviral activityDrug efavirenzClass drugsInhibitorsViral polymeraseDrugsEnzyme inhibition kineticsResistant mutantsConclusive evidenceTranscriptasePoint mutationsCovalent inhibitorsHIVPatientsNevirapineEfavirenzStructural and Preclinical Studies of Computationally-Designed Non-nucleoside Reverse Transcriptase Inhibitors for Treating HIV infection
Kudalkar SN, Beloor J, Chan AH, Lee WG, Jorgensen WL, Kumar P, Anderson KS. Structural and Preclinical Studies of Computationally-Designed Non-nucleoside Reverse Transcriptase Inhibitors for Treating HIV infection. Molecular Pharmacology 2017, 91: mol.116.107755. PMID: 28167742, PMCID: PMC5363707, DOI: 10.1124/mol.116.107755.Peer-Reviewed Original ResearchConceptsNon-nucleoside reverse transcriptase inhibitorBALB/c miceReverse transcriptase inhibitorHIV infectionC miceTranscriptase inhibitorAntiviral activityCompound INew non-nucleoside reverse transcriptase inhibitorHIV-1 non-nucleoside reverse transcriptase inhibitorDetectable acute toxicityTreating HIV InfectionSingle intraperitoneal doseAnti-HIV-1 potencyMT-2 cellsDrug-resistant variantsCompound IISerum residence timeAnti-viral potencyHIV-1 RTClinical benefitClinical efficacyIntraperitoneal doseWild-type HIV-1 RTPlasma clearance
2016
Computer-aided discovery of anti-HIV agents
Jorgensen WL. Computer-aided discovery of anti-HIV agents. Bioorganic & Medicinal Chemistry 2016, 24: 4768-4778. PMID: 27485603, PMCID: PMC5114837, DOI: 10.1016/j.bmc.2016.07.039.Peer-Reviewed Original Research
2015
Discovery and crystallography of bicyclic arylaminoazines as potent inhibitors of HIV-1 reverse transcriptase
Lee WG, Frey KM, Gallardo-Macias R, Spasov KA, Chan AH, Anderson KS, Jorgensen WL. Discovery and crystallography of bicyclic arylaminoazines as potent inhibitors of HIV-1 reverse transcriptase. Bioorganic & Medicinal Chemistry Letters 2015, 25: 4824-4827. PMID: 26166629, PMCID: PMC4607639, DOI: 10.1016/j.bmcl.2015.06.074.Peer-Reviewed Original ResearchStructure-Based Evaluation of Non-nucleoside Inhibitors with Improved Potency and Solubility That Target HIV Reverse Transcriptase Variants
Frey KM, Puleo DE, Spasov KA, Bollini M, Jorgensen WL, Anderson KS. Structure-Based Evaluation of Non-nucleoside Inhibitors with Improved Potency and Solubility That Target HIV Reverse Transcriptase Variants. Journal Of Medicinal Chemistry 2015, 58: 2737-2745. PMID: 25700160, PMCID: PMC4378236, DOI: 10.1021/jm501908a.Peer-Reviewed Original Research
2014
Crystallographic and Receptor Binding Characterization of Plasmodium falciparum Macrophage Migration Inhibitory Factor Complexed to Two Potent Inhibitors
Pantouris G, Rajasekaran D, Garcia AB, Ruiz VG, Leng L, Jorgensen WL, Bucala R, Lolis EJ. Crystallographic and Receptor Binding Characterization of Plasmodium falciparum Macrophage Migration Inhibitory Factor Complexed to Two Potent Inhibitors. Journal Of Medicinal Chemistry 2014, 57: 8652-8656. PMID: 25268646, PMCID: PMC4207548, DOI: 10.1021/jm501168q.Peer-Reviewed Original ResearchA mechanistic and structural investigation of modified derivatives of the diaryltriazine class of NNRTIs targeting HIV-1 reverse transcriptase
Mislak AC, Frey KM, Bollini M, Jorgensen WL, Anderson KS. A mechanistic and structural investigation of modified derivatives of the diaryltriazine class of NNRTIs targeting HIV-1 reverse transcriptase. Biochimica Et Biophysica Acta 2014, 1840: 2203-2211. PMID: 24726448, PMCID: PMC4061246, DOI: 10.1016/j.bbagen.2014.04.001.Peer-Reviewed Original ResearchConceptsSolvent interfaceStructure-based drug designCatalytic site geometryPhysiochemical propertiesFuture inhibitor developmentTransient-state kinetic analysisImproved pharmacological propertiesImproved pharmacological profileAzine ringPolymerization stepMorpholine derivativesCrystal structureLow nanomolar potencyDrug designSubstituentsStructural investigationsSite geometryImproved physiochemical propertiesNew inhibitorsNanomolar potencyLow nanomolar antiviral activityDerivativesStructural basisStructural analysisNon-nucleoside inhibitors
2013
Optimization of diarylazines as anti-HIV agents with dramatically enhanced solubility
Bollini M, Cisneros JA, Spasov KA, Anderson KS, Jorgensen WL. Optimization of diarylazines as anti-HIV agents with dramatically enhanced solubility. Bioorganic & Medicinal Chemistry Letters 2013, 23: 5213-5216. PMID: 23937980, PMCID: PMC3759246, DOI: 10.1016/j.bmcl.2013.06.091.Peer-Reviewed Original Research
2012
Optimization of benzyloxazoles as non-nucleoside inhibitors of HIV-1 reverse transcriptase to enhance Y181C potency
Bollini M, Gallardo-Macias R, Spasov KA, Tirado-Rives J, Anderson KS, Jorgensen WL. Optimization of benzyloxazoles as non-nucleoside inhibitors of HIV-1 reverse transcriptase to enhance Y181C potency. Bioorganic & Medicinal Chemistry Letters 2012, 23: 1110-1113. PMID: 23298809, PMCID: PMC3561933, DOI: 10.1016/j.bmcl.2012.11.115.Peer-Reviewed Original ResearchCrystal Structures of HIV‑1 Reverse Transcriptase with Picomolar Inhibitors Reveal Key Interactions for Drug Design
Frey KM, Bollini M, Mislak AC, Cisneros J, Gallardo-Macias R, Jorgensen WL, Anderson KS. Crystal Structures of HIV‑1 Reverse Transcriptase with Picomolar Inhibitors Reveal Key Interactions for Drug Design. Journal Of The American Chemical Society 2012, 134: 19501-19503. PMID: 23163887, PMCID: PMC3518392, DOI: 10.1021/ja3092642.Peer-Reviewed Original ResearchVirtual Screening and Optimization Yield Low-Nanomolar Inhibitors of the Tautomerase Activity of Plasmodium falciparum Macrophage Migration Inhibitory Factor
Dahlgren MK, Garcia AB, Hare AA, Tirado-Rives J, Leng L, Bucala R, Jorgensen WL. Virtual Screening and Optimization Yield Low-Nanomolar Inhibitors of the Tautomerase Activity of Plasmodium falciparum Macrophage Migration Inhibitory Factor. Journal Of Medicinal Chemistry 2012, 55: 10148-10159. PMID: 23067344, PMCID: PMC3509768, DOI: 10.1021/jm301269s.Peer-Reviewed Original ResearchConceptsImmune responsePlasmodium falciparum macrophage migration inhibitory factorInhibitory factorMacrophage migration inhibitory factorTautomerase activityMacrophage migratory inhibitory factorMigration inhibitory factorHost immune responseMalaria infectionSmall molecule inhibitorsCytokine activityHuman MIFHuman cytokinesPlasmodium falciparum orthologuePfMIFInhibitorsLow nanomolar inhibitorsScreeningVirtual screeningCytokinesEnzymatic siteActivityInfectionSmall‐Molecule Inhibitors of the Interaction between the E3 Ligase VHL and HIF1α
Buckley DL, Gustafson JL, Van Molle I, Roth AG, Tae HS, Gareiss PC, Jorgensen WL, Ciulli A, Crews CM. Small‐Molecule Inhibitors of the Interaction between the E3 Ligase VHL and HIF1α. Angewandte Chemie International Edition 2012, 51: 11463-11467. PMID: 23065727, PMCID: PMC3519281, DOI: 10.1002/anie.201206231.Peer-Reviewed Original Research
2011
Computationally-Guided Optimization of a Docking Hit to Yield Catechol Diethers as Potent Anti-HIV Agents
Bollini M, Domaoal RA, Thakur VV, Gallardo-Macias R, Spasov KA, Anderson KS, Jorgensen WL. Computationally-Guided Optimization of a Docking Hit to Yield Catechol Diethers as Potent Anti-HIV Agents. Journal Of Medicinal Chemistry 2011, 54: 8582-8591. PMID: 22081993, PMCID: PMC3258498, DOI: 10.1021/jm201134m.Peer-Reviewed Original Research
2010
Receptor agonists of macrophage migration inhibitory factor
Jorgensen WL, Gandavadi S, Du X, Hare AA, Trofimov A, Leng L, Bucala R. Receptor agonists of macrophage migration inhibitory factor. Bioorganic & Medicinal Chemistry Letters 2010, 20: 7033-7036. PMID: 20971005, PMCID: PMC2989669, DOI: 10.1016/j.bmcl.2010.09.118.Peer-Reviewed Original ResearchOptimization of N-benzyl-benzoxazol-2-ones as receptor antagonists of macrophage migration inhibitory factor (MIF)
Hare AA, Leng L, Gandavadi S, Du X, Cournia Z, Bucala R, Jorgensen WL. Optimization of N-benzyl-benzoxazol-2-ones as receptor antagonists of macrophage migration inhibitory factor (MIF). Bioorganic & Medicinal Chemistry Letters 2010, 20: 5811-5814. PMID: 20728358, PMCID: PMC2939296, DOI: 10.1016/j.bmcl.2010.07.129.Peer-Reviewed Original ResearchConceptsMacrophage migration inhibitory factorCytokine macrophage migration inhibitory factorMigration inhibitory factorHuman synovial fibroblastsReceptor CD74Receptor antagonistSynovial fibroblastsInhibitory factorAdditional studiesERK1/2 phosphorylationCell proliferationTautomerase activityAntagonistPotent inhibitorBinding assaysInhibitorsAssaysInflammationCD74
2009
Chemical Control over Immune Recognition: A Class of Antibody-Recruiting Small Molecules That Target Prostate Cancer
Murelli RP, Zhang AX, Michel J, Jorgensen WL, Spiegel DA. Chemical Control over Immune Recognition: A Class of Antibody-Recruiting Small Molecules That Target Prostate Cancer. Journal Of The American Chemical Society 2009, 131: 17090-17092. PMID: 19888723, PMCID: PMC2794306, DOI: 10.1021/ja906844e.Peer-Reviewed Original ResearchConceptsSmall moleculesFundamental chemical principlesBifunctional small moleculesProstate-specific membrane antigenProstate cancer cellsProstate cancerChemical principlesBiological evaluationCrystallographic dataMoleculesAmerican male populationTernary complexLNCaP human prostate cancer cellsCancer cellsHuman effector cellsHuman prostate cancer cellsCancer-related deathAntibody-dependent killingClasses of antibodiesHigh therapeutic potentialNovel classAntibody-recruiting moleculesHuman immune systemAnti-DNP antibodiesEffector cellsIn Silico Improvement of β3-Peptide Inhibitors of p53•hDM2 and p53•hDMX
Michel J, Harker EA, Tirado-Rives J, Jorgensen WL, Schepartz A. In Silico Improvement of β3-Peptide Inhibitors of p53•hDM2 and p53•hDMX. Journal Of The American Chemical Society 2009, 131: 6356-6357. PMID: 19415930, PMCID: PMC2754742, DOI: 10.1021/ja901478e.Peer-Reviewed Original Research
2007
From Docking False-Positive to Active Anti-HIV Agent
Barreiro G, Kim JT, Guimarães CR, Bailey CM, Domaoal RA, Wang L, Anderson KS, Jorgensen WL. From Docking False-Positive to Active Anti-HIV Agent. Journal Of Medicinal Chemistry 2007, 50: 5324-5329. PMID: 17918923, PMCID: PMC2575345, DOI: 10.1021/jm070683u.Peer-Reviewed Original Research