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M9460579.TXT
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1994-06-25
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Document 0579
DOCN M9460579
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).