title: Simultaneous mutations at Tyr-181 and Tyr-188 in HIV-1 reverse transcriptase prevents inhibition of RNA-dependent DNA polymerase activity by the bisheteroarylpiperazine (BHAP) U-90152s.
abstract: The replacement of either Tyr-181 or Tyr-188 of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) by the corresponding HIV-2 RT amino acids Ile-181 or Leu-188 is known to result in active mutant enzymes (Y181I; Y188L) with virtual loss of sensitivity towards three structural classes of nonnucleoside RT inhibitors; L-697,661, nevirapine, and TIBO R82913. The bisheteroarylpiperazine (BHAP) U-90152S, a highly specific inhibitor (IC50, 0.29 +/- 0.01 microM) of HIV-1 RT, inhibited the recombinant Y181I and Y188L HIV-1 RT mutants with IC50 values of 3.6 +/- 0.15 microM and 0.71 +/- 0.02 microM, respectively. Construction and in vitro analysis of double mutants Y181I/Y188L and Y181C/Y188L of HIV-1 RT showed > 150-fold resistance to U-90152S. An HIV-2 RT mutant containing amino acids 176-190 from HIV-1 RT acquired full sensitivity to U-90152S (IC50, 0.26 +/- 0.01 microM). It is concluded that simultaneous mutations at Tyr-181 and Tyr-188 of HIV-1 RT promotes resistance to U-90152S.
authors.affiliation: Upjohn Laboratories, Kalamazoo, MI 49001, USA.
authors.forename: N
authors.initials: N
authors.lastname: Fan
authors.forename: K B
authors.initials: KB
authors.lastname: Rank
authors.forename: D B
authors.initials: DB
authors.lastname: Evans
authors.forename: R C
authors.initials: RC
authors.lastname: Thomas
authors.forename: W G
authors.initials: WG
authors.lastname: Tarpley
authors.forename: S K
authors.initials: SK
authors.lastname: Sharma
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology; D001583:Benzoxazoles / Q000494:pharmacology; D003001:Cloning, Molecular; D020008:Delavirdine; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D015498:HIV-2 / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D007700:Kinetics; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D019829:Nevirapine; D010879:Piperazines / Q000494:pharmacology*; D017354:Point Mutation; D011725:Pyridines / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology; D012194:RNA-Directed DNA Polymerase / Q000302:isolation & purification / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors; D014443:Tyrosine
chemical_list: D000998:Antiviral Agents; D001583:Benzoxazoles; D007093:Imidazoles; D007211:Indoles; D010879:Piperazines; D011725:Pyridines; D011728:Pyridones; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D018894:Reverse Transcriptase Inhibitors; D001569:Benzodiazepines; D014443:Tyrosine; C076516:L-697661; C067413:R-82913; D019829:Nevirapine; D020008:Delavirdine; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase