Discovery of TSAO derivatives with an unusual HIV-1 activity/resistance profile.
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.
de Castro
Sonia
S
Instituto de Química Médica (C.S.I.C.), Juan de la Cierva 3, Madrid, Spain.
García-Aparicio
Carlos
C
Van Laethem
Kristel
K
Gago
Federico
F
Lobatón
Esther
E
De Clercq
Erik
E
Balzarini
Jan
J
Camarasa
María-José
MJ
Velázquez
Sonsoles
S
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
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D013141:Spiro Compounds; D054303:HIV Reverse Transcriptase; D013936:Thymidine