Document 1099
 DOCN  M9591099
 TI    Resistance to 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine
       derivatives is generated by mutations at multiple sites in the HIV-1
       reverse transcriptase.
 DT    9509
 AU    Buckheit RW Jr; Fliakas-Boltz V; Yeagy-Bargo S; Weislow O; Mayers DL;
       Boyer PL; Hughes SH; Pan BC; Chu SH; Bader JP; Virology Research Group,
       Southern Research Institute, Frederick; Research Center, Maryland 21701,
       USA.
 SO    Virology. 1995 Jun 20;210(1):186-93. Unique Identifier : AIDSLINE
       MED/95313352
 AB    Virus isolates resistant to
       1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) and a highly
       potent HEPT derivative,
       [1-benzyloxymethyl-5-ethyl-6-(alpha-pyridylthio)uracil] (NSC 648400,
       E-BPTU), were selected in cell culture. Cross-resistance evaluation
       indicated that the two drug-resistant virus isolates were phenotypically
       distinct from one another although each of the virus isolates was
       resistant to both of the HEPT derivatives. The virus isolate resistant
       to NSC 648400 had a single amino acid change in the reverse
       transcriptase (Y181C) which resulted in cross-resistance to all of the
       nonnucleoside reverse transcriptase inhibitors evaluated, with the
       exception of calanolide A. The NSC 648400-resistant virus isolate
       exhibited 15-fold enhanced sensitivity to calanolide A. The virus
       isolate selected in the presence of HEPT exhibited a single amino acid
       change (P236L) which was not cross-resistant to other nonnucleoside RT
       inhibitors tested with the exception of the two HEPT derivatives. This
       HEPT-resistant virus isolate exhibited enhanced sensitivity (5- to
       10-fold) to thiazolobenzimidazole. We have used both virus isolates with
       defined single amino acid changes in the RT and bacterially expressed
       RTs with site-directed amino acid substitutions to test the effects of a
       wide variety of mutations on the activity of NSC 648400. Single
       mutations at amino acids 101, 103, 106, 181, or 236 yielded virus with
       high resistance (> 20-fold) to NSC 648400, while lower levels of
       resistance were seen with mutations at amino acids 98, 100, or 108.
       These results suggest that several changes in the conformation of the
       nonnucleoside inhibitor binding site of the HIV-1 reverse transcriptase
       can affect the inhibitory activity of the HEPT class of compounds.
 DE    Antiviral Agents/*PHARMACOLOGY  Cell Line  Comparative Study
       Dose-Response Relationship, Drug  Drug Resistance, Microbial  Human
       HIV-1/*DRUG EFFECTS/ENZYMOLOGY/ISOLATION & PURIF  HIV-2/DRUG EFFECTS
       *Mutagenesis, Site-Directed  Pyridines/PHARMACOLOGY  Recombinant
       Proteins/ANTAGONISTS & INHIB/BIOSYNTHESIS  Reverse
       Transcriptase/*ANTAGONISTS & INHIB/BIOSYNTHESIS  Structure-Activity
       Relationship  Support, U.S. Gov't, Non-P.H.S.  Support, U.S. Gov't,
       P.H.S.  Thymine/*ANALOGS & DERIVATIVES/PHARMACOLOGY  Uracil/ANALOGS &
       DERIVATIVES/PHARMACOLOGY  Zidovudine/PHARMACOLOGY  JOURNAL ARTICLE

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