Autor: |
Olmsted, R A, Slade, D E, Kopta, L A, Poppe, S M, Poel, T J, Newport, S W, Rank, K B, Biles, C, Morge, R A, Dueweke, T J, Yagi, Y, Romero, D L, Thomas, R C, Sharma, S K, Tarpley, W G |
Zdroj: |
The Journal of Virology; June 1996, Vol. 70 Issue: 6 p3698-3705, 8p |
Abstrakt: |
The (alkylamino)piperidine bis(heteroaryl)piperizines (AAP-BHAPs) are a new class of human immunodeficiency virus type 1 (HIV-1)-specific inhibitors which were identified by targeted screening of recombinant reverse transcriptase (RT) enzymes carrying key nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-conferring mutations and NNRTI-resistant variants of HIV-1. Phenotypic profiling of the two most potent AAP-BHAPs, U-95133 and U-104489, against in vitro-selected drug-resistant HIV-1 variants carrying the NNRTI resistance-conferring mutation (Tyr->Cys) at position 181 of the HIV-1 RT revealed submicromolar 90% inhibitory concentration estimates for these compounds. Moreover, U-104489 demonstrated potent activity against BHA-P-resistant HIV-1MF harboring the Pro-236->Leu RT substitution and significantly suppressed the replication of clinical isolates of HIV-1 resistant to both delavirdine (BHAP U-90152T) and zidovudine. Biochemical and phenotypic characterization of AAP-BHAPresistant HIV-1IIIB variants revealed that high-level resistance to the AAP-BHAPs was mediated by a Gly-190->Glu substitution in RT, which had a deleterious effect on the integrity and enzymatic activity of virion-associated RT heterodimers, as well as the replication capacity of these resistant viruses. |
Databáze: |
Supplemental Index |
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