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-qPCRCovalent and noncovalent strategies for targeting Lys102 in HIV-1 reverse transcriptase
Prucha G, Henry S, Hollander K, Carter Z, Spasov K, Jorgensen W, Anderson K. Covalent and noncovalent strategies for targeting Lys102 in HIV-1 reverse transcriptase. European Journal Of Medicinal Chemistry 2023, 262: 115894. PMID: 37883896, PMCID: PMC10872499, DOI: 10.1016/j.ejmech.2023.115894.Peer-Reviewed Original ResearchNoncanonical HPV carcinogenesis drives radiosensitization of head and neck tumors
Schrank T, Kothari A, Weir W, Stepp W, Rehmani H, Liu X, Wang X, Sewell A, Li X, Tasoulas J, Kim S, Yarbrough G, Xie Y, Flamand Y, Marur S, Hayward M, Wu D, Burtness B, Anderson K, Baldwin A, Yarbrough W, Issaeva N. Noncanonical HPV carcinogenesis drives radiosensitization of head and neck tumors. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2216532120. PMID: 37523561, PMCID: PMC10410762, DOI: 10.1073/pnas.2216532120.Peer-Reviewed Original ResearchConceptsNF-κB-related genesEstrogen receptor alpha expressionDeintensification of therapyTreatment-related morbidityTumor-infiltrating CD4Receptor alpha expressionHPV carcinogenesisRadiosensitization of headOncogenic subtypesPIK3CA alterationsHNSCC tumorsPatient outcomesNeck tumorsT cellsTreatment responseHNSCC cellsTherapeutic intensityAtypical featuresIndependent cohortAlpha expressionNF-κBActive tumorTNF receptorTumorsPatient data
2014
Current Perspectives on HIV-1 Antiretroviral Drug Resistance
Iyidogan P, Anderson K. Current Perspectives on HIV-1 Antiretroviral Drug Resistance. Viruses 2014, 6: 4095-4139. PMID: 25341668, PMCID: PMC4213579, DOI: 10.3390/v6104095.Peer-Reviewed Original Research
2012
Pre-steady state kinetic analysis of cyclobutyl derivatives of 2′-deoxyadenosine 5′-triphosphate as inhibitors of HIV-1 reverse transcriptase
Kim J, Wang L, Li Y, Becnel K, Frey K, Garforth S, Prasad V, Schinazi R, Liotta D, Anderson K. Pre-steady state kinetic analysis of cyclobutyl derivatives of 2′-deoxyadenosine 5′-triphosphate as inhibitors of HIV-1 reverse transcriptase. Bioorganic & Medicinal Chemistry Letters 2012, 22: 4064-4067. PMID: 22595174, PMCID: PMC3362660, DOI: 10.1016/j.bmcl.2012.04.078.Peer-Reviewed Original ResearchBalancing Antiviral Potency and Host Toxicity: Identifying a Nucleotide Inhibitor with an Optimal Kinetic Phenotype for HIV-1 Reverse Transcriptase
Sohl C, Kasiviswanathan R, Kim J, Pradere U, Schinazi R, Copeland W, Mitsuya H, Baba M, Anderson K. Balancing Antiviral Potency and Host Toxicity: Identifying a Nucleotide Inhibitor with an Optimal Kinetic Phenotype for HIV-1 Reverse Transcriptase. Molecular Pharmacology 2012, 82: 125-133. PMID: 22513406, PMCID: PMC3382833, DOI: 10.1124/mol.112.078758.Peer-Reviewed Original ResearchConceptsNucleoside reverse transcriptase inhibitorsHost toxicityClinical trialsReverse transcriptaseTreatment of HIV infectionMinimal host toxicityUnique toxicity profilePhase II clinical trialReverse transcriptase inhibitorsII clinical trialsHIV-1 reverse transcriptaseWild-typeAntiretroviral efficacyHIV infectionToxicity profileTranscriptase inhibitorsHIV-1Molecular mechanismsTreat HIVMechanisms of toxicityMitochondrial toxicityMolecular mechanisms of toxicityAntiviral potencyViral target proteinsThymidine analog
2010
[d4U]-Spacer-[HI-236] double-drug inhibitors of HIV-1 reverse-transcriptase
Younis Y, Hunter R, Muhanji C, Hale I, Singh R, Bailey C, Sullivan T, Anderson K. [d4U]-Spacer-[HI-236] double-drug inhibitors of HIV-1 reverse-transcriptase. Bioorganic & Medicinal Chemistry 2010, 18: 4661-4673. PMID: 20605472, PMCID: PMC2964380, DOI: 10.1016/j.bmc.2010.05.025.Peer-Reviewed Original Researchmip1 containing mutations associated with mitochondrial disease causes mutagenesis and depletion of mtDNA in Saccharomyces cerevisiae
Stumpf J, Bailey C, Spell D, Stillwagon M, Anderson K, Copeland W. mip1 containing mutations associated with mitochondrial disease causes mutagenesis and depletion of mtDNA in Saccharomyces cerevisiae. Human Molecular Genetics 2010, 19: 2123-2133. PMID: 20185557, PMCID: PMC2865372, DOI: 10.1093/hmg/ddq089.Peer-Reviewed Original ResearchConceptsMitochondrial dysfunctionHuman pol gammaSaccharomyces cerevisiae orthologAssociated with mitochondrial diseasesDecreased polymerase activityAtaxia-neuropathy syndromeDepletion of mtDNADNA polymerase gammaDisease-associated mutationsMutations in vivoIncreased nucleotide poolOrthologous human mutationMtDNA replication defectsMtDNA mutagenesisMtDNA replicationProgressive external ophthalmoplegiaSaccharomyces cerevisiaeMutant strainMutant enzymesPol gammaHuman orthologPolymerase gammaConserved regionMtDNA depletionMtDNA
2007
Epidermal Growth Factor Receptor Mutants from Human Lung Cancers Exhibit Enhanced Catalytic Activity and Increased Sensitivity to Gefitinib
Mulloy R, Ferrand A, Kim Y, Sordella R, Bell D, Haber D, Anderson K, Settleman J. Epidermal Growth Factor Receptor Mutants from Human Lung Cancers Exhibit Enhanced Catalytic Activity and Increased Sensitivity to Gefitinib. Cancer Research 2007, 67: 2325-2330. PMID: 17332364, DOI: 10.1158/0008-5472.can-06-4293.Peer-Reviewed Original ResearchConceptsEpidermal growth factor receptorEpidermal growth factor receptor mutantMultiple levels in vivoIn vitro kinase assayEpidermal growth factor receptor functionPurified recombinant proteinWild-type epidermal growth factor receptorSensitivity to kinase inhibitionNon-small cell lung cancerCOOH-terminal tyrosineHuman non-small cell lung cancerIncreased sensitivity to gefitinibSensitivity to gefitinibCell lung cancerAutophosphorylation activityGrowth factor receptorCell-based studiesEGFR kinase inhibitorsCytoplasmic domainRecombinant proteinsKinase assayEnzyme functionDownstream effectorsMutantsKinase activity[d4U]-butyne-[HI-236] as a non-cleavable, bifunctional NRTI/NNRTI HIV-1 reverse-transcriptase inhibitor
Hunter R, Muhanji C, Hale I, Bailey C, Basavapathruni A, Anderson K. [d4U]-butyne-[HI-236] as a non-cleavable, bifunctional NRTI/NNRTI HIV-1 reverse-transcriptase inhibitor. Bioorganic & Medicinal Chemistry Letters 2007, 17: 2614-2617. PMID: 17317163, DOI: 10.1016/j.bmcl.2007.01.107.Peer-Reviewed Original Research
2006
Developing novel nonnucleoside HIV-1 reverse transcriptase inhibitors: beyond the butterfly.
Basavapathruni A, Anderson K. Developing novel nonnucleoside HIV-1 reverse transcriptase inhibitors: beyond the butterfly. Current Pharmaceutical Design 2006, 12: 1857-65. PMID: 16724952, DOI: 10.2174/138161206776873617.Peer-Reviewed Original ResearchConceptsNonnucleoside reverse transcriptase inhibitorsReverse transcriptase inhibitorsTranscriptase inhibitorsHuman immunodeficiency virus type 1 infectionResistance to nonnucleoside reverse transcriptase inhibitorsTreatment of human immunodeficiency virus type 1 infectionType 1 infectionFood and Drug AdministrationU.S. Food and Drug AdministrationCombination therapyDevelopment of resistanceMechanism of actionHIV-1 reverse transcriptase inhibitorsDrug AdministrationNonnucleosideNonnucleoside HIV-1 reverse transcriptase inhibitorNonnucleoside inhibitorsFeatures of inhibitionPotential new inhibitorsInhibitorsAmino acid substitutionsBiochemical featuresMolecular mechanismsNew inhibitorsAcid substitutions
2004
Relationship between Antiviral Activity and Host Toxicity: Comparison of the Incorporation Efficiencies of 2′,3′-Dideoxy-5-Fluoro-3′-Thiacytidine-Triphosphate Analogs by Human Immunodeficiency Virus Type 1 Reverse Transcriptase and Human Mitochondrial DNA Polymerase
Feng J, Murakami E, Zorca S, Johnson A, Johnson K, Schinazi R, Furman P, Anderson K. Relationship between Antiviral Activity and Host Toxicity: Comparison of the Incorporation Efficiencies of 2′,3′-Dideoxy-5-Fluoro-3′-Thiacytidine-Triphosphate Analogs by Human Immunodeficiency Virus Type 1 Reverse Transcriptase and Human Mitochondrial DNA Polymerase. Antimicrobial Agents And Chemotherapy 2004, 48: 1300-1306. PMID: 15047533, PMCID: PMC375312, DOI: 10.1128/aac.48.4.1300-1306.2004.Peer-Reviewed Original ResearchConceptsHuman mitochondrial DNA polymeraseMitochondrial DNA polymeraseDNA-DNAPolymerase gammaHuman immunodeficiency virusDNA polymerasePrimer-templateHuman mitochondrial DNA polymerase gammaPre-steady-state kinetic analysisMitochondrial DNA polymerase gammaDNA polymerase gammaMolecular mechanism of inhibitionHIV-1Treatment of human immunodeficiency virusExonuclease activityDNA-RNAReverse transcriptaseFood and Drug AdministrationClinical trial studyMolecular mechanismsMechanism of inhibitionHuman immunodeficiency virus type 1 reverse transcriptaseEnzymatic assayImmunodeficiency virusPolymerase
2003
Characterization of Novel Reverse Transcriptase and Other RNA-associated Catalytic Activities by Human DNA Polymerase γ IMPORTANCE IN MITOCHONDRIAL DNA REPLICATION*
Murakami E, Feng J, Lee H, Hanes J, Johnson K, Anderson K. Characterization of Novel Reverse Transcriptase and Other RNA-associated Catalytic Activities by Human DNA Polymerase γ IMPORTANCE IN MITOCHONDRIAL DNA REPLICATION*. Journal Of Biological Chemistry 2003, 278: 36403-36409. PMID: 12857740, DOI: 10.1074/jbc.m306236200.Peer-Reviewed Original ResearchConceptsMtDNA genomeMtDNA replicationPol gammaInitiation of mtDNA replicationRNA-primed DNA synthesisHuman mitochondrial DNA polymeraseMitochondrial DNA polymeraseReverse transcriptionDNA synthesis activityPhysiologically relevant ratesMitochondrial DNARibonucleotide incorporationProofreading activitySingle ribonucleotidesHeteroduplex intermediatesRibonucleotide triphosphatesRNA templateDNA primersDNA polymeraseReverse transcriptaseDNA excisionMtDNAAccessory subunitsDNA synthesisEnzymatic pathways
2002
The Kinetic Mechanism of the Human Bifunctional Enzyme ATIC (5-Amino-4-imidazolecarboxamide Ribonucleotide Transformylase/Inosine 5′-Monophosphate Cyclohydrolase) A SURPRISING LACK OF SUBSTRATE CHANNELING*
Bulock K, Beardsley G, Anderson K. The Kinetic Mechanism of the Human Bifunctional Enzyme ATIC (5-Amino-4-imidazolecarboxamide Ribonucleotide Transformylase/Inosine 5′-Monophosphate Cyclohydrolase) A SURPRISING LACK OF SUBSTRATE CHANNELING*. Journal Of Biological Chemistry 2002, 277: 22168-22174. PMID: 11948179, DOI: 10.1074/jbc.m111964200.Peer-Reviewed Original ResearchConceptsCyclohydrolase reactionProduction of inosine monophosphateRelease of tetrahydrofolateSteady-state kinetic techniquesStopped-flow absorbanceBifunctional enzymeActive siteBifunctional proteinSubstrate channelingInosine 5'-monophosphateCyclohydrolaseEnzymatic activityChemotherapeutic targetEnzyme reaction pathwayInosine monophosphateKinetic mechanismFormyltransferaseProteinEnzymeKinetic analysisPathwayKinetic advantageKinetic evidenceKinetic techniquesRibonucleotides
2001
Deoxythioguanosine triphosphate impairs HIV replication: a new mechanism for an old drug
KRYNETSKAIA N, FENG J, KRYNETSKI E, GARCIA J, PANETTA J, ANDERSON K, EVANS W. Deoxythioguanosine triphosphate impairs HIV replication: a new mechanism for an old drug. The FASEB Journal 2001, 15: 1902-1908. PMID: 11532970, DOI: 10.1096/fj.01-0124com.Peer-Reviewed Original ResearchConceptsAnti-retroviral agentsHIV replicationHIV-1 reverse transcriptaseReverse transcriptaseTreatment of HIVHuman lymphocyte culturesDifferent medicationsHost lymphocytesAdditive cytotoxicityHIV-1Old drugsLymphocyte culturesActive metaboliteHuman lymphocytesMinimal toxicityLymphocytesThioguanineSubstantial inhibitionTreatmentInhibitionHIV proteaseEarly stagesMedicationsHIVPatientsToxicity of Antiviral Nucleoside Analogs and the Human Mitochondrial DNA Polymerase*
Johnson A, Ray A, Hanes J, Suo Z, Colacino J, Anderson K, Johnson K. Toxicity of Antiviral Nucleoside Analogs and the Human Mitochondrial DNA Polymerase*. Journal Of Biological Chemistry 2001, 276: 40847-40857. PMID: 11526116, DOI: 10.1074/jbc.m106743200.Peer-Reviewed Original ResearchInsights into the Molecular Mechanism of Mitochondrial Toxicity by AIDS Drugs*
Feng J, Johnson A, Johnson K, Anderson K. Insights into the Molecular Mechanism of Mitochondrial Toxicity by AIDS Drugs*. Journal Of Biological Chemistry 2001, 276: 23832-23837. PMID: 11328813, DOI: 10.1074/jbc.m101156200.Peer-Reviewed Original ResearchMeSH KeywordsAcquired Immunodeficiency SyndromeAnti-HIV AgentsCytidine TriphosphateDeoxycytosine NucleotidesDideoxynucleotidesDNADNA Polymerase gammaDNA ReplicationDNA, MitochondrialDNA-Directed DNA PolymeraseExodeoxyribonucleasesHumansKineticsLamivudineMitochondriaNucleic Acid Synthesis InhibitorsReverse Transcriptase InhibitorsZalcitabineConceptsPol gammaHuman mitochondrial DNA polymeraseHuman pol gammaMitochondrial DNA replicationMitochondrial DNA polymeraseToxicity of nucleoside analogsCytosine analogsMechanism of mitochondrial toxicityExonuclease activityDNA primersDNA replicationDNA polymeraseNucleoside analogsRate of excisionStructure/function relationshipsMolecular mechanismsLong-term administrationToxic inhibitorsExonucleaseTreatment of AIDSPolymeraseClinical toxicityMitochondrial toxicityDNAPolMechanism of Action of 1-β-d-2,6-Diaminopurine Dioxolane, a Prodrug of the Human Immunodeficiency Virus Type 1 Inhibitor 1-β-d-Dioxolane Guanosine
Furman P, Jeffrey J, Kiefer L, Feng J, Anderson K, Borroto-Esoda K, Hill E, Copeland W, Chu C, Sommadossi J, Liberman I, Schinazi R, Painter G. Mechanism of Action of 1-β-d-2,6-Diaminopurine Dioxolane, a Prodrug of the Human Immunodeficiency Virus Type 1 Inhibitor 1-β-d-Dioxolane Guanosine. Antimicrobial Agents And Chemotherapy 2001, 45: 158-165. PMID: 11120959, PMCID: PMC90254, DOI: 10.1128/aac.45.1.158-165.2001.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine Deaminase InhibitorsAnti-HIV AgentsBone Marrow CellsCells, CulturedDioxolanesDNA, ViralDrug Resistance, MicrobialEnzyme InhibitorsGuanosineHIV-1HumansLactic AcidMicroscopy, ElectronMitochondriaNucleic Acid Synthesis InhibitorsProdrugsPurine NucleosidesReverse Transcriptase InhibitorsConceptsDiaminopurine dioxolaneDXG-TPNucleoside reverse transcriptase inhibitorHuman immunodeficiency virus type 1Peripheral blood mononuclear cellsImmunodeficiency virus type 1Blood mononuclear cellsReverse transcriptase inhibitorAdenosine deaminaseVirus type 1Alternative substrate inhibitorsHIV-1 RTMechanism of actionWater-soluble prodrugMononuclear cellsDioxolane guanosineTranscriptase inhibitorType 1CEM cellsInhibitor-1Mitochondrial toxicityHuman DNA polymerase alphaCalf adenosine deaminaseInhibitorsDNA polymerase gamma
2000
Insights into the HER-2 Receptor Tyrosine Kinase Mechanism and Substrate Specificity Using a Transient Kinetic Analysis †
Jan A, Johnson E, Diamonti A, Carraway K, Anderson K. Insights into the HER-2 Receptor Tyrosine Kinase Mechanism and Substrate Specificity Using a Transient Kinetic Analysis †. Biochemistry 2000, 39: 9786-9803. PMID: 10933796, DOI: 10.1021/bi9924922.Peer-Reviewed Original ResearchConceptsReceptor tyrosine kinasesRecombinant proteinsTyrosine kinaseSerine/threonine kinaseProtein kinase familyReceptor-like proteinCatalytic mechanismDegenerate peptide libraryStopped-flow fluorescence studiesIntracellular tyrosine kinase domainTyrosine kinase mechanismTyrosine kinase domainState kinetic analysisThreonine kinaseKinase familyCatalytic subunitKinase domainPhosphorylation stateSubstrate specificityProtein modificationNucleotide interactionsKinase mechanismConformational changesTransient kinetic investigationsHER-2/erbB