Document 0198
 DOCN  M9460198
 TI    Mutational analysis of residue 190 of human immunodeficiency virus type
       1 reverse transcriptase.
 DT    9408
 AU    Kleim JP; Bender R; Kirsch R; Meichsner C; Paessens A; Riess G; Hoechst
       AG, SBU Antiinfectives Research, Frankfurt, Germany.
 SO    Virology. 1994 May 1;200(2):696-701. Unique Identifier : AIDSLINE
       MED/94233733
 AB    S-2720 and other members of the quinoline/quinoxaline class of
       HIV-1-specific nonnucleoside reverse transcriptase inhibitors (NNRTIs)
       select for a glycine to glutamate substitution at residue 190 (Gly 190
       Glu) of the reverse transcriptase (RT), when drug-resistant viruses are
       generated in cell culture. This mutation has not been described to
       appear upon selection for resistant viral variants using derivatives of
       any other class of NNRTIs. Notably, the RNA-dependent DNA polymerase
       activity of the Gly 190 Glu mutant enzyme is drastically diminished with
       respect to the wild-type RT. We describe here the effects of other amino
       acid substitutions at position 190 of the RT that were introduced by
       using site-directed mutagenesis. Polymerase activities and sensitivities
       to inhibition by a number of NNRTIs were determined for the different RT
       mutants. In general, an inverse correlation was found between the
       enzymatic activity and increasing length of the side chain, whereas the
       size of the residue and the level of resistance to NNRTIs appeared to be
       positively related. Double mutants, which contain the Gly 190 Glu
       mutation together with substitutions that confer resistance to other RT
       inhibitors, were all shown to possess severely diminished polymerase
       activity.
 DE    Antiviral Agents/*PHARMACOLOGY  Base Sequence
       Benzodiazepines/PHARMACOLOGY  Benzoxazoles/PHARMACOLOGY  Comparative
       Study  Drug Resistance, Microbial/GENETICS  DNA Mutational Analysis
       HIV-1/*ENZYMOLOGY/GENETICS  Imidazoles/PHARMACOLOGY
       Indoles/PHARMACOLOGY  Molecular Sequence Data  Mutagenesis,
       Site-Directed  Piperazines/PHARMACOLOGY  Pyridines/PHARMACOLOGY
       Pyridones/PHARMACOLOGY  Quinoxalines/PHARMACOLOGY  Reverse
       Transcriptase/*ANTAGONISTS & INHIB/DRUG EFFECTS/*GENETICS  Selection
       (Genetics)  Structure-Activity Relationship  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).