title: Pre-steady state kinetic analysis of cyclobutyl derivatives of 2'-deoxyadenosine 5'-triphosphate as inhibitors of HIV-1 reverse transcriptase.
abstract: Pre-steady state kinetic analysis was utilized for biochemical evaluation of a series of cyclobutyl adenosine nucleotide analogs with HIV-1 RT(WT). The phosphonyl-diphosphate form of the cyclobutyl nucleotide, 5, was the most efficiently incorporated of the series. Nucleotide 5 was fourfold more efficiently incorporated than the FDA approved TFV-DP by RT(WT). The kinetics of incorporation for 5 using the drug resistant mutant enzyme K65R was also determined. Compound 5 was threefold more efficiently incorporated compared to TFV-DP with RT(K65R). These results demonstrate cyclobutyl adenosine analogs can act as substrates for incorporation by HIV-1 RT and be a potential scaffold for HIV inhibitors.
authors.affiliation: Department of Pharmacology, School of Medicine, Yale University, SHM B350B, 333 Cedar Street, New Haven, CT 06520-8066, USA.
authors.forename: Jiae
authors.initials: J
authors.lastname: Kim
authors.forename: Ligong
authors.initials: L
authors.lastname: Wang
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Li
authors.forename: Kimberlynne D
authors.initials: KD
authors.lastname: Becnel
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Frey
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Garforth
authors.forename: Vinayaka R
authors.initials: VR
authors.lastname: Prasad
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Schinazi
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Liotta
authors.forename: Karen S
authors.initials: KS
authors.lastname: Anderson
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D003503:Cyclobutanes / Q000138:chemical synthesis* / Q000494:pharmacology; D017931:DNA Primers; D003838:Deoxyadenine Nucleotides / Q000138:chemical synthesis* / Q000494:pharmacology; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007700:Kinetics; D009154:Mutation; D021141:Nucleic Acid Amplification Techniques; D063065:Organophosphonates / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D000068698:Tenofovir
chemical_list: D019380:Anti-HIV Agents; D003503:Cyclobutanes; D017931:DNA Primers; D003838:Deoxyadenine Nucleotides; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D000225:Adenine; C026600:2'-deoxyadenosine triphosphate