title: Discovery of TSAO derivatives with an unusual HIV-1 activity/resistance profile.
abstract: The very first TSAO derivative that lacks the 4''-amino group at the 3'-spiro moiety (compound 3) has been prepared and the effect of this modification on the activity/resistance profile has been evaluated. This molecule proved HIV-1 specific (NNRTI-characteristic). A mixture of wild-type and V106V/A or L234L/I mutations were found in the RT of some, but not all compound 3-resistant virus strains. Compound 3 does not select for the TSAO-specific E138K mutation in the RT. However, the compound markedly lost its antiviral potential against a variety of virus strains that contain NNRTI-characteristic mutations in RT including E138K. The deaminated TSAO compound must fit differently in the HIV-1 RT enzyme than its prototype TSAO-m(3)T.
authors.affiliation: Instituto de Química Médica (C.S.I.C.), Juan de la Cierva 3, Madrid, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: de Castro
authors.forename: Carlos
authors.initials: C
authors.lastname: García-Aparicio
authors.forename: Kristel
authors.initials: K
authors.lastname: Van Laethem
authors.forename: Federico
authors.initials: F
authors.lastname: Gago
authors.forename: Esther
authors.initials: E
authors.lastname: Lobatón
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: María-José
authors.initials: MJ
authors.lastname: Camarasa
authors.forename: Sonsoles
authors.initials: S
authors.lastname: Velázquez
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000235:genetics; D015497:HIV-1 / Q000201:enzymology / Q000254:growth & development*; D015498:HIV-2 / Q000201:enzymology / Q000254:growth & development*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013936:Thymidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D013141:Spiro Compounds; D054303:HIV Reverse Transcriptase; D013936:Thymidine