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 diethersDesign, 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
2014
Recent Findings on the Mechanisms Involved in Tenofovir Resistance
Iyidogan P, Anderson K. Recent Findings on the Mechanisms Involved in Tenofovir Resistance. Antiviral Chemistry And Chemotherapy 2014, 23: 217-222. PMID: 23744599, PMCID: PMC4077986, DOI: 10.3851/imp2628.Peer-Reviewed Original ResearchConceptsReverse transcriptase inhibitorsDrug resistanceResistance mechanismsNon-nucleoside reverse transcriptase inhibitorsHIV-1 infectionLong-term efficacyMechanism of RTSynergistic antiviral effectTenofovir resistanceAntiretroviral agentsCombination therapyTreatment failureAntiviral synergySafety profileTranscriptase inhibitorsHIV-1TenofovirClinical useAntiviral effectTherapyViral sequencesNucleotide analoguesRegimensEfavirenzCurrent 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 Research
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
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 stagesMedicationsHIVPatientsMechanism 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 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
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 ResearchConceptsHIV-1 reverse transcriptaseFTC-TPClinical trialsReverse transcriptaseOngoing clinical trialsTreatment of AIDSAntiretroviral activityClinical potencyViral replicationBeta 2Triphosphate formNucleoside inhibitorsDifferential potencyRNA-dependent DNA synthesisEnhanced potencyTrialsPotencyMolecular mechanismsMechanistic studiesDNA synthesisInhibitorsTranscriptaseFTC
1998
Implication 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 ResearchPre-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 Research
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
1992
Mechanism and fidelity of HIV reverse transcriptase.
Kati W, Johnson K, Jerva L, Anderson K. Mechanism and fidelity of HIV reverse transcriptase. Journal Of Biological Chemistry 1992, 267: 25988-25997. PMID: 1281479, DOI: 10.1016/s0021-9258(18)35706-5.Peer-Reviewed Original ResearchMeSH KeywordsBase SequenceBinding SitesDeoxyribonucleotidesDNAEscherichia coliHIV Reverse TranscriptaseHIV-1KineticsModels, BiologicalMolecular Sequence DataNucleic Acid HeteroduplexesOligodeoxyribonucleotidesOligoribonucleotidesRecombinant ProteinsRNARNA-Directed DNA PolymeraseSubstrate SpecificityTemplates, GeneticConceptsRNA templateRNA/DNA heteroduplexesRNA cleavageDuplex DNAPre-steady state burstRate of DNA polymerizationDNA-dependent polymerasesRNA cleavage productsBinding of dNTPSingle nucleotide incorporationRibonuclease domainRNA-dependentVirus reverse transcriptasePublished crystal structureNucleotide incorporationNucleoside triphosphatesHuman immunodeficiency virus reverse transcriptaseDNTP complexDissociation of DNADNA polymerizationReverse transcriptaseDATPHeteroduplexCleavage productsRNA