Abstract: Further investigation of the structure-activity relationships of close congeners of these novel (alkylamino)piperidine BHAPs (AAP-BHAPs) led to the synthesis of several compounds possessing the desired phenotype (e.g., activity against recombinant RTs carrying the Y181C and P236L substitutions).
Selection conditions affect the evolution of specific mutations in the reverse transcriptase gene associated with resistance to DMP 266.
Abstract: RESULTS: Passage in MT-2 cells resulted in accumulation of three substitutions in RT (V179D, L1001, Y181C) after 24 passages associated with 1000-fold reduced susceptibility to DMP 266.
Biophysical Characterization of Novel DNA Aptamers against K103N/Y181C Double Mutant HIV-1 Reverse Transcriptase.
Abstract: Apparently the Tyr181 --> Cys mutation eliminates favorable contacts of the aromatic ring of the tyrosine and the bou.
Abstract: Mutant HIV-1 RT, containing Cys in place of Tyr at position 181 (Tyrl81Cys), is highly resistant to many NNRTIs and HIV-1 variants containing this mutation have been selected in both cell culture and clinical trials.
Abstract: Some positional changes in the polypeptide backbone of the beta6-beta10-beta9 sheet containing residue 181 are observed when the Tyr181Cys and wild-type complexes are compared, particularlty near residue Val179 of beta9.
Abstract: When the structure of the Tyr181Cys mutant HIV-1 RT in complex with 8-Cl TIBO is compared with the corresponding structure containing wild-t
Replication of a pre-existing resistant HIV-1 subpopulation in vivo after introduction of a strong selective drug pressure.
Abstract: We analysed proviral DNA from nine previously untreated participants in a nevirapine study for the presence of the nevirapine resistance-conferring tyrosine to cysteine substitution at codon 181 of HIV-1 reverse transcriptase.
Novel non-nucleoside inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. 4. 2-Substituted dipyridodiazepinones as potent inhibitors of both wild-type and cysteine-181 HIV-1 reverse transcriptase enzymes.
Abstract: An evaluation, against Y181C RT, of previously described analogs of nevirapine revealed that the 2-chlorodipyridodiazepinone 16 is an effective inhibitor of this mutant enzyme.
Abstract: In addition, the substitution pattern at C-4, N-5, and N-11 of the dipyridodiazepinone ring system optimum for inhibition of both wild-type and Y181C RT is no longer the 4-methyl-11-cyclopropyl substitution preferred against the wild-type enzyme but rather the 5-methyl-11-ethyl (or 11-cyclopropyl) pattern.
Abstract: The detailed examination of the structure-activity relationship of 2-substituted dipyridodiazepinones presented below shows that combined activity against the wild-type and Y181C enzymes is achieved with aryl substituents at the 2-position of the tricyclic ring system.
Abstract: The maj
Novel non-nucleoside inhibitors of human immunodeficiency virus type 1 reverse transcriptase. 5. 4-Substituted and 2,4-disubstituted analogs of nevirapine.
Abstract: Attempts to combine these results with the recent discovery that 2-substituents enhance activity against the Y181C mutant led to a few compounds with moderate activity against both enzymes.
Abstract: Furthermore certain derivatives appear to inhibit the Y181C mutant RT.
Differential activities of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives against different human immunodeficiency virus type 1 mutant strains.
PMID: 7540384
1995
Antimicrobial agents and chemotherapy
Abstract: A series of 23 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives that were highly potent inhibitors of wild-type human immunodeficiency virus type 1 strain IIIB (HIV-1/IIIB) replication in CEM cells were evaluated against a panel of HIV-1 mutant strains containing the replacement of leucine by isoleucine at position 100 (100-Leu-->Ile), 103-Lys-->Asn, 106-Val-->Ala, 138-Glu-->Lys, 181-Tyr-->Cys, 181-Tyr-->Ile, or 188-Tyr-->His in their reverse transcriptase (RT).
Resistance to 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives is generated by mutations at multiple sites in the HIV-1 reverse transcriptase.
Abstract: 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.
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: Construction and in vitro analysis of double mutants Y181I/Y188L and Y181C/Y188L of HIV-1 RT showed > 150-fold resistance to U-90152S.
Structure-activity and cross-resistance evaluations of a series of human immunodeficiency virus type-1-specific compounds related to oxathiin carboxanilide.
PMID: 8593008
1995
Antimicrobial agents and chemotherapy
Abstract: A resistant virus isolate containing both Y181C combination with calanolide A, an NNRTI which retains activity against virus with the single Y181C mutation, UC10 rapidly selected a virus isolate with the K103N mutation.
Abstract: The results with isolates selected in cell culture indicate that the carboxanilide compounds interact with the RT at two vulnerable sites, selecting UC-resistant virus isolates with the Y-to-C mutation at position 181 (Y181C) or the L100I substitution.
HIV mutation literature information.
PMID: 
1996
Journal of medicinal chemistry
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