2012
Balancing 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
mip1 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
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
2001
Toxicity 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 ResearchMeSH KeywordsBase SequenceDNA Polymerase gammaDNA PrimersDNA-Directed DNA PolymeraseHumansKineticsMitochondriaProdrugsRecombinant ProteinsReverse Transcriptase InhibitorsInsights 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 toxicityDNAPol