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 ResearchMeSH KeywordsAnti-HIV AgentsCatecholsHIV Reverse TranscriptaseHIV-1IndolizinesNaphthalenesReverse Transcriptase InhibitorsStructure-Activity RelationshipConceptsHIV 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 ResearchMeSH KeywordsAnti-HIV AgentsDrug DesignHIV Reverse TranscriptaseHIV-1Models, MolecularReverse Transcriptase InhibitorsStructure-Activity Relationship
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 ResearchMeSH KeywordsAnti-HIV AgentsDideoxynucleosidesDNA Polymerase gammaDNA-Directed DNA PolymeraseDNA, MitochondrialHIV InfectionsHIV Reverse TranscriptaseHIV-1HumansKineticsNucleotidesReverse Transcriptase InhibitorsStavudineConceptsNucleoside 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 ResearchMeSH KeywordsAnti-HIV AgentsBinding SitesCell LineComputer SimulationDrug DesignHIV Reverse TranscriptaseHIV-1HumansPolyethylene GlycolsPyridinesReverse Transcriptase InhibitorsThiourea
2008
C-2-Aryl O-substituted HI-236 derivatives as non-nucleoside HIV-1 reverse-transcriptase inhibitors
Hunter R, Younis Y, Muhanji C, Curtin T, Naidoo K, Petersen M, Bailey C, Basavapathruni A, Anderson K. C-2-Aryl O-substituted HI-236 derivatives as non-nucleoside HIV-1 reverse-transcriptase inhibitors. Bioorganic & Medicinal Chemistry 2008, 16: 10270-10280. PMID: 18996020, PMCID: PMC2639753, DOI: 10.1016/j.bmc.2008.10.048.Peer-Reviewed Original ResearchConceptsThiourea derivativesHI-236C-2 arylationC-2 oxygenStructure-activity profilePhenyl ringAnti-HIV activityNNRTI pocketC-2Drug designCell-free RT assaysDocking modelThioureaDerivativesInhibitory activityBifunctional inhibitorsImproved leadsPhenylAutoDockDockingRingCompoundsPocketSpatial characteristicsMT-2 cell cultures
2007
[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 ResearchMeSH KeywordsAnti-HIV AgentsDrug DesignDrug Resistance, ViralHIV InfectionsHIV Reverse TranscriptaseHumansModels, MolecularMolecular StructureReverse Transcriptase InhibitorsConceptsNonnucleoside 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
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 toxicityDNAPolMECHANISTIC 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 ResearchMeSH KeywordsAnti-HIV AgentsDeoxyguanine NucleotidesDNA PrimersHIV Reverse TranscriptaseReverse Transcriptase InhibitorsRNATemplates, GeneticMechanism 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
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 ResearchMeSH KeywordsAnimalsAnti-HIV AgentsDrug DesignHIV Reverse TranscriptaseHIV-1HumansReverse Transcriptase InhibitorsConceptsCatalytic 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 substratesEnzymeMechanism of Inhibition of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase by d4TTP: an Equivalent Incorporation Efficiency Relative to the Natural Substrate dTTP
Vaccaro J, Parnell K, Terezakis S, Anderson K. Mechanism of Inhibition of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase by d4TTP: an Equivalent Incorporation Efficiency Relative to the Natural Substrate dTTP. Antimicrobial Agents And Chemotherapy 2000, 44: 217-221. PMID: 10602755, PMCID: PMC89660, DOI: 10.1128/aac.44.1.217-221.2000.Peer-Reviewed Original ResearchMeSH KeywordsAnti-HIV AgentsBase SequenceDNAHIV Reverse TranscriptaseHumansMolecular Sequence DataReverse Transcriptase InhibitorsRibonuclease HThymine NucleotidesConceptsHIV-1HIV-1 RTHuman immunodeficiency virus type 1Immunodeficiency virus type 1Target human immunodeficiency virus type 1Inhibition of HIV-1 RTNatural substrateVirus type 1Pre-steady-state kinetic analysisNucleoside analogue inhibitorsDNA synthesisRNA-dependent DNA synthesisAIDS patientsPrimer-template complexHuman immunodeficiency virus type 1 reverse transcriptaseNucleoside triphosphate analoguesType 1Mechanism of inhibitionD4TTPIncorporation efficiencyDTTPDNATriphosphate analoguesAnalogue inhibitorsInhibition
1999
Mechanistic 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 ResearchMeSH KeywordsBase SequenceEmtricitabineHIV Reverse TranscriptaseHIV-1HumansKineticsLamivudineMolecular Sequence DataOligodeoxyribonucleotidesReverse Transcriptase InhibitorsSubstrate SpecificityVirus ReplicationZalcitabineConceptsHIV-1 reverse transcriptaseFTC-TPClinical trialsReverse transcriptaseOngoing clinical trialsTreatment of AIDSAntiretroviral activityClinical potencyViral replicationBeta 2Triphosphate formNucleoside inhibitorsDifferential potencyRNA-dependent DNA synthesisEnhanced potencyTrialsPotencyMolecular mechanismsMechanistic studiesDNA synthesisInhibitorsTranscriptaseFTC
1997
Pre-Steady-State Kinetic Characterization of Wild Type and 3‘-Azido-3‘-deoxythymidine (AZT) Resistant Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Implication of RNA Directed DNA Polymerization in the Mechanism of AZT Resistance †
Kerr S, Anderson K. Pre-Steady-State Kinetic Characterization of Wild Type and 3‘-Azido-3‘-deoxythymidine (AZT) Resistant Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Implication of RNA Directed DNA Polymerization in the Mechanism of AZT Resistance †. Biochemistry 1997, 36: 14064-14070. PMID: 9369478, DOI: 10.1021/bi9713862.Peer-Reviewed Original ResearchMeSH KeywordsAnti-HIV AgentsDideoxynucleotidesDrug ResistanceHIV Reverse TranscriptaseHIV-1KineticsMutationReverse Transcriptase InhibitorsRibonuclease HThymidine MonophosphateThymine NucleotidesZidovudine
1996
HIV-1 Reverse Transcriptase Resistance to Nonnucleoside Inhibitors †
Spence R, Anderson K, Johnson K. HIV-1 Reverse Transcriptase Resistance to Nonnucleoside Inhibitors †. Biochemistry 1996, 35: 1054-1063. PMID: 8547241, DOI: 10.1021/bi952058+.Peer-Reviewed Original ResearchMeSH KeywordsAntiviral AgentsBinding SitesDeoxyadenine NucleotidesDNADrug ResistanceHIV Reverse TranscriptaseNevirapinePyridinesReverse Transcriptase InhibitorsRNA-Directed DNA PolymeraseConceptsMutant enzymesPre-steady-state techniquesSingle nucleotide incorporationWild-type complexMaximum incorporation rateNucleotide incorporationEnzyme complexDuplex DNAAffinity 2Cysteine mutationsTwo-step bindingWild-typeConformational changesDecreased affinityEnzymePresence of nevirapineInhibitor resistanceMutationsIncorporation rateY181C mutationWild-type RTReverse transcriptaseHIV-1NevirapineY181C
1995
Mechanism of Inhibition of HIV-1 Reverse Transcriptase by Nonnucleoside Inhibitors
Spence R, Kati W, Anderson K, Johnson K. Mechanism of Inhibition of HIV-1 Reverse Transcriptase by Nonnucleoside Inhibitors. Science 1995, 267: 988-993. PMID: 7532321, PMCID: PMC7526747, DOI: 10.1126/science.7532321.Peer-Reviewed Original ResearchConceptsActive site catalytic residuesPre-steady-state kinetic analysisNucleotide-induced conformational changesInterfere with nucleotide bindingPre-steady-state burstEnzyme-DNA complexPre-steady-stateReverse transcriptasePresence of saturating concentrationsCatalytic residuesNucleotide bindingNucleoside triphosphatesDNA polymerizationNucleotide analogsHydrophobic pocketMechanism of inhibitionNonnucleoside inhibitorsConformational changesNoncompetitive inhibitorInhibition of HIV-1 reverse transcriptaseKinetic analysisHIV-1 reverse transcriptaseSaturating concentrationsTranscriptaseInhibitors