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 ResearchConceptsHIV-1 reverse transcriptaseT cell assaysReverse transcriptaseNon-nucleoside inhibitorsLow nanomolar activityPotent NNRTIsEnzyme inhibitionInhibitorsTranscriptaseNNRTI
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
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
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 ResearchConceptsHIV-1 reverse transcriptaseReverse transcriptaseHIV drugsMetabolic activationNatural nucleoside configurationNucleoside inhibitorsMechanistic basisImplication 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 ResearchConceptsHIV-1 reverse transcriptaseReverse transcriptaseHIV-1 RTRNA/DNATranscriptasePresent studyEquilibrium dissociation constantsFurther supportCurrent understandingDNA/DNAPre-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