2023
Exploring novel HIV‐1 reverse transcriptase inhibitors with drug‐resistant mutants: A double mutant surprise
Hollander K, Chan A, Frey K, Hunker O, Ippolito J, Spasov K, Yeh Y, Jorgensen W, Ho Y, Anderson K. Exploring novel HIV‐1 reverse transcriptase inhibitors with drug‐resistant mutants: A double mutant surprise. Protein Science 2023, 32: e4814. PMID: 37861472, PMCID: PMC10659932, DOI: 10.1002/pro.4814.Peer-Reviewed Original ResearchConceptsHIV drug developmentReverse transcriptaseHIV-1 reverse transcriptaseNew RT inhibitorsDrug-resistant mutantsLifelong treatmentHIV-1 reverseRT inhibitorsClinical isolatesPreclinical candidateResistance mutationsResistant variantsSuccessful managementMolecular cloneFirst-generation inhibitorsDrug developmentV106ASame mutationCandidate compoundsGeneration inhibitorsInhibitorsKey targetCatechol diethersCovalent 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 ResearchDesign, synthesis, and biological testing of biphenylmethyloxazole inhibitors targeting HIV-1 reverse transcriptase
Carter Z, Hollander K, Spasov K, Anderson K, Jorgensen W. Design, synthesis, and biological testing of biphenylmethyloxazole inhibitors targeting HIV-1 reverse transcriptase. Bioorganic & Medicinal Chemistry Letters 2023, 84: 129216. PMID: 36871704, PMCID: PMC10278203, DOI: 10.1016/j.bmcl.2023.129216.Peer-Reviewed Original Research
2015
Human PrimPol: A Novel Mechanism of Antiviral Toxicity
Mislak A, Anderson K. Human PrimPol: A Novel Mechanism of Antiviral Toxicity. The FASEB Journal 2015, 29 DOI: 10.1096/fasebj.29.1_supplement.710.23.Peer-Reviewed Original ResearchNucleoside reverse transcriptase inhibitorsAntiviral toxicityHIV-1HIV-1-infected patientsNRTI-associated mitochondrial toxicityDaily drug regimensHIV-1 infectionLife-long administrationReverse transcriptase inhibitorsReduced viral loadReverse transcriptasePrevent viral transmissionDrug regimensViral loadTranscriptase inhibitorsRelated morbidityInfected patientsSevere mitochondrial dysfunctionSide effectsPatient adherenceViral replicationMechanisms of toxicityMitochondrial toxicityViral transmissionPatients
2013
Correction to Bifunctional Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Mechanism and Proof-of-Concept as a Novel Therapeutic Design Strategy
Bailey C, Sullivan T, Iyidogan P, Tirado-Rives J, Chung R, Ruiz-Caro J, Mohamed E, Jorgensen W, Hunter R, Anderson K. Correction to Bifunctional Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Mechanism and Proof-of-Concept as a Novel Therapeutic Design Strategy. Journal Of Medicinal Chemistry 2013, 56: 8953-8953. PMCID: PMC4301842, DOI: 10.1021/jm401535f.Peer-Reviewed Original ResearchDesign, Synthesis, and Antiviral Evaluation of Chimeric Inhibitors of HIV Reverse Transcriptase
Iyidogan P, Sullivan T, Chordia M, Frey K, Anderson K. Design, Synthesis, and Antiviral Evaluation of Chimeric Inhibitors of HIV Reverse Transcriptase. ACS Medicinal Chemistry Letters 2013, 4: 1183-1188. PMID: 24900627, PMCID: PMC4027223, DOI: 10.1021/ml4002979.Peer-Reviewed Original ResearchH-phosphonatesLow nanomolar antiviral potencyReduced HIV replicationInhibitors of HIV reverse transcriptasePolymethylene linkerHIV replicationTMC derivativesAnti-HIV agentsAntiviral evaluationAntiviral activity profileChimeric inhibitorsHIV reverse transcriptaseCell-based assaysAntiviral potencyReverse transcriptaseIC50 valuesCellular levelNucleosideInhibitorsThymidinePolymethylene
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
2007
FEP-Guided Selection of Bicyclic Heterocycles in Lead Optimization for Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase [J. Am. Chem. Soc. 2006, 128, 15372−15373].
Kim J, Hamilton A, Bailey C, Domaoal R, Wang L, Anderson K, Jorgensen W. FEP-Guided Selection of Bicyclic Heterocycles in Lead Optimization for Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase [J. Am. Chem. Soc. 2006, 128, 15372−15373]. Journal Of The American Chemical Society 2007, 129: 3027-3027. DOI: 10.1021/ja076881s.Peer-Reviewed Original Research
2006
Optimization of Diarylamines as Non‐Nucleoside Inhibitors of HIV‐1 Reverse Transcriptase.
Ruiz‐Caro J, Basavapathruni A, Kim J, Bailey C, Wang L, Anderson K, Hamilton A, Jorgensen W. Optimization of Diarylamines as Non‐Nucleoside Inhibitors of HIV‐1 Reverse Transcriptase. ChemInform 2006, 37: no-no. DOI: 10.1002/chin.200618152.Peer-Reviewed Original Research
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
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 stagesMedicationsHIVPatientsMECHANISTIC STUDIES TO UNDERSTAND THE INHIBITION OF WILD TYPE AND MUTANT HIV-1 REVERSE TRANSCRIPTASE BY CARBOVIR-TRIPHOSPHATE
Ray A, Anderson K. MECHANISTIC STUDIES TO UNDERSTAND THE INHIBITION OF WILD TYPE AND MUTANT HIV-1 REVERSE TRANSCRIPTASE BY CARBOVIR-TRIPHOSPHATE. Nucleosides Nucleotides & Nucleic Acids 2001, 20: 1247-1250. PMID: 11562995, DOI: 10.1081/ncn-100002528.Peer-Reviewed Original Research
2000
An analysis of the catalytic cycle of HIV-1 reverse transcriptase: opportunities for chemotherapeutic intervention based on enzyme inhibition.
Furman P, Painter G, Anderson K. An analysis of the catalytic cycle of HIV-1 reverse transcriptase: opportunities for chemotherapeutic intervention based on enzyme inhibition. Current Pharmaceutical Design 2000, 6: 547-67. PMID: 10788596, DOI: 10.2174/1381612003400777.Peer-Reviewed Original ResearchConceptsCatalytic cycleIntrinsic binding affinityHIV-1 reverse transcriptaseCatalytic complexChemical catalysisBinding affinityCatalysisMolecular forcesReverse transcriptase inhibitorsAllosteric siteClasses of approved drugsNon-nucleoside reverse transcriptase inhibitorsTranscriptase inhibitorsNucleoside reverse transcriptase inhibitorsSite of inhibitionEnzyme inhibitionReverse transcriptaseAlternative substratesEnzyme
1999
Initiation of Minus-Strand DNA Synthesis by Human Immunodeficiency Virus Type 1 Reverse Transcriptase †
Vaccaro J, Singh H, Anderson K. Initiation of Minus-Strand DNA Synthesis by Human Immunodeficiency Virus Type 1 Reverse Transcriptase †. Biochemistry 1999, 38: 15978-15985. PMID: 10625465, DOI: 10.1021/bi990945x.Peer-Reviewed Original ResearchConceptsHIV-1 reverse transcriptaseDNA/DNA substratesReverse transcriptaseHuman immunodeficiency virus type 1 reverse transcriptaseType 1 reverse transcriptasePrimer-template substrateDNA synthesisMinus-strand DNA synthesisConcentrations of dCTPDNA/RNADeoxynucleotide incorporationMolecular mechanismsTranscriptaseSteady-state releaseInitiationHigh affinityRNAReleaseStrand DNA synthesisMechanistic studies show that (−)‐FTC‐TP is a better inhibitor of HIV‐1 reverse transcriptase than 3TC‐TP
Feng J, Shi J, Schinazi R, Anderson K. Mechanistic studies show that (−)‐FTC‐TP is a better inhibitor of HIV‐1 reverse transcriptase than 3TC‐TP. The FASEB Journal 1999, 13: 1511-1517. PMID: 10463941, DOI: 10.1096/fasebj.13.12.1511.Peer-Reviewed Original ResearchConceptsHIV-1 reverse transcriptaseFTC-TPClinical trialsReverse transcriptaseOngoing clinical trialsTreatment of AIDSAntiretroviral activityClinical potencyViral replicationBeta 2Triphosphate formNucleoside inhibitorsDifferential potencyRNA-dependent DNA synthesisEnhanced potencyTrialsPotencyMolecular mechanismsMechanistic studiesDNA synthesisInhibitorsTranscriptaseFTCMechanistic Studies Examining the Efficiency and Fidelity of DNA Synthesis by the 3TC-Resistant Mutant (184V) of HIV-1 Reverse Transcriptase †
Feng J, Anderson K. Mechanistic Studies Examining the Efficiency and Fidelity of DNA Synthesis by the 3TC-Resistant Mutant (184V) of HIV-1 Reverse Transcriptase †. Biochemistry 1999, 38: 9440-9448. PMID: 10413520, DOI: 10.1021/bi990709m.Peer-Reviewed Original ResearchConceptsHIV-1 reverse transcriptaseM184V RTHIV-1 virusWild-type HIV-1 reverse transcriptaseReverse transcriptaseDNA-dependent DNA polymerizationStrong antiviral effectRNA-dependent DNA polymerizationCombination therapyAntiviral effectMethionine 184Mutant reverse transcriptaseMutant HIV-1 reverse transcriptaseRT fidelityCorresponding DNA templateSingle amino acid substitutionMolecular mechanismsAmino acid substitutionsVirusDNA synthesisTranscriptaseAcid substitutionsHigh levelsClinicTherapy
1998
Mechanistic Studies Comparing the Incorporation of (+) and (−) Isomers of 3TCTP by HIV-1 Reverse Transcriptase †
Feng J, Anderson K. Mechanistic Studies Comparing the Incorporation of (+) and (−) Isomers of 3TCTP by HIV-1 Reverse Transcriptase †. Biochemistry 1998, 38: 55-63. PMID: 9890882, DOI: 10.1021/bi982340r.Peer-Reviewed Original ResearchImplication of the tRNA Initiation Step for Human Immunodeficiency Virus Type 1 Reverse Transcriptase in the Mechanism of 3‘-Azido-3‘-deoxythymidine (AZT) Resistance †
Vaccaro J, Anderson K. Implication of the tRNA Initiation Step for Human Immunodeficiency Virus Type 1 Reverse Transcriptase in the Mechanism of 3‘-Azido-3‘-deoxythymidine (AZT) Resistance †. Biochemistry 1998, 37: 14189-14194. PMID: 9760256, DOI: 10.1021/bi9810353.Peer-Reviewed Original ResearchConceptsHIV-1 reverse transcriptaseLong-term AZT therapyReverse transcriptaseHuman immunodeficiency virus type 1 reverse transcriptaseAZT-resistant reverse transcriptaseType 1 reverse transcriptaseNew pharmacological basisAZT therapyAIDS patientsWild-type HIV-1 reverse transcriptasePharmacological basisAZT resistanceClinical resistanceMutant HIV-1 reverse transcriptaseDrug resistanceViral isolatesLack of correlationPatientsPrimer-template substrateAIDS drugsTranscriptase
1997
RNA Dependent DNA Replication Fidelity of HIV-1 Reverse Transcriptase: Evidence of Discrimination between DNA and RNA Substrates †
Kerr S, Anderson K. RNA Dependent DNA Replication Fidelity of HIV-1 Reverse Transcriptase: Evidence of Discrimination between DNA and RNA Substrates †. Biochemistry 1997, 36: 14056-14063. PMID: 9369477, DOI: 10.1021/bi971385+.Peer-Reviewed Original Research