Document 0009
 DOCN  M9550009
 TI    Resistance of human immunodeficiency virus type 1 to acyclic
       6-phenylselenenyl- and 6-phenylthiopyrimidines.
 DT    9505
 AU    Nguyen MH; Schinazi RF; Shi C; Goudgaon NM; McKenna PM; Mellors JW;
       Department of Medicine, University of Pittsburgh School of; Medicine,
       Pennsylvania.
 SO    Antimicrob Agents Chemother. 1994 Oct;38(10):2409-14. Unique Identifier
       : AIDSLINE MED/95142586
 AB    Acyclic 6-phenylselenenyl- and 6-phenylthiopyrimidine derivatives are
       potent and specific inhibitors of human immunodeficiency virus type 1
       (HIV-1). The development of in vitro resistance to two derivatives,
       5-ethyl-1-(ethoxymethyl)-(6-phenylthio)-uracil (E-EPU), was evaluated by
       serial passage of HIV-1 in increasing concentrations of inhibitor. HIV-1
       variants exhibiting > 500-fold resistance to E-EPSeU and E-EPU were
       isolated after sequential passage in 1, 5, and 10 microM inhibitor. The
       resistant variants exhibited coresistance to related acyclic
       6-substituted pyrimidines and the HIV-1-specific inhibitors
       (+)-(5S)-4,5,6,7-tetrahydro-5- pyrimidines and the HIV-1-specific
       inhibitors (+)-(5S)-4,5,6,7-tetrahydro-5-
       methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk]benzodiazepin-2(1H)-
       thione (TIBO R82150) and nevirapine, but remained susceptible to
       3'-azido-3'-deoxythymidine, 2',3'-dideoxycytidine, 2',3'-dideoxyinosine,
       and phosphonoformic acid. DNA sequence analysis of reverse transcriptase
       (RT) derived from E-EPSeU-resistant virus identified a Tyr (TAT)-to-Cys
       (TGT) mutation at either codon 188 (Cys-188; 9 of 15 clones) or codon
       181 (Cys-181; 5 of 15 clones). The same amino acid changes were found in
       RT from E-EPU-resistant virus, but the Cys-181 mutation was more common
       (9 of 10 clones) than the Cys-188 mutation (1 of 10 clones).
       Site-specific mutagenesis and production of mutant recombinant viruses
       demonstrated that both the Cys-181 and Cys-188 mutations cause
       resistance to E-EPSeU and E-EPU. Of the two mutations, the Cys-188
       substitution produced greater E-EPSeU and E-EPU resistance.(ABSTRACT
       TRUNCATED AT 250 WORDS)
 DE    Antiviral Agents/*PHARMACOLOGY  Drug Resistance/GENETICS  Human
       HIV-1/*DRUG EFFECTS/GENETICS  Mutation  Organoselenium
       Compounds/*PHARMACOLOGY  Structure-Activity Relationship
       Uracil/*ANALOGS & DERIVATIVES/PHARMACOLOGY  Zidovudine/PHARMACOLOGY
       JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
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