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A mutation in the 3' region of the human immunodeficiency virus type 1 reverse transcriptase (Y318F) associated with nonnucleoside reverse transcriptase inhibitor resistance 下载免费PDF全文
Harrigan PR Salim M Stammers DK Wynhoven B Brumme ZL McKenna P Larder B Kemp SD 《Journal of virology》2002,76(13):6836-6840
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Characterization of a subtype D human immunodeficiency virus type 1 isolate that was obtained from an untreated individual and that is highly resistant to nonnucleoside reverse transcriptase inhibitors 下载免费PDF全文
Gao Y Paxinos E Galovich J Troyer R Baird H Abreha M Kityo C Mugyenyi P Petropoulos C Arts EJ 《Journal of virology》2004,78(10):5390-5401
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Ambrose Z Boltz V Palmer S Coffin JM Hughes SH Kewalramani VN 《Journal of virology》2004,78(24):13553-13561
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The P236L Delavirdine-Resistant Human Immunodeficiency Virus Type 1 Mutant Is Replication Defective and Demonstrates Alterations in both RNA 5′-End- and DNA 3′-End-Directed RNase H Activities 下载免费PDF全文
Peter Gerondelis Richard H. Archer Chockalingam Palaniappan Richard C. Reichman Philip J. Fay Robert A. Bambara Lisa M. Demeter 《Journal of virology》1999,73(7):5803-5813
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Arranz ME Díaz JA Ingate ST Witvrouw M Pannecouque C Balzarini J De Clercq E Vega S 《Bioorganic & medicinal chemistry》1999,7(12):2811-2822
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F M Uckun C Mao S Pendergrass D Maher D Zhu L Tuel-Ahlgren T K Venkatachalam 《Bioorganic & medicinal chemistry letters》1999,9(18):2721-2726
We have replaced the pyridyl ring of trovirdine with an alicyclic cyclohexenyl, adamantyl or cis-myrtanyl ring. Only the cyclohexenyl-containing thiourea compound N-[2-(1-cyclohexenyl)ethyl]-N'-[2-(5-bromopyridyl)]- thiourea (HI-346) (as well as its chlorine-substituted derivative N-[2-(1-cyclohexenyl)ethyl]-N'-[2-(5-chloropyridyl)]- thiourea/HI-445) showed RT inhibitory activity. HI-346 and HI-445 effectively inhibited recombinant RT with better IC50 values than other anti-HIV agents tested. The ranking order of efficacy in cell-free RT inhibition assays was: HI-346 (IC50 = 0.4 microM) > HI-445 (IC50 = 0.5 microM) > trovirdine (IC50 = 0.8 microM) > MKC-442 (IC5 = 0.8 microM) = delavirdine (IC50 = 1.5 microM) > nevirapine (IC50 = 23 microM). In accord with this data, both compounds inhibited the replication of the drug-sensitive HIV-1 strain HTLV(IIIB) with better IC50 values than other anti-HIV agents tested. The ranking order of efficacy in cellular HIV-1 inhibition assays was: HI-445 = HI-346 (IC50 = 3 nM) > MKC-442 (IC50 = 4 nM) = AZT (IC50 = 4 nM) > trovirdine (IC50 = 7 nM) > delavirdine (IC50 = 9 nM) > nevirapine (IC50 = 34 nM). Surprisingly, the lead compounds HI-346 and HI-445 were 3-times more effective against the multidrug resistant HIV-1 strain RT-MDR with a V106A mutation (as well as additional mutations involving the RT residues 74V,41L, and 215Y) than they were against HTLV(IIIB) with wild-type RT. HI-346 and HI-445 were 20-times more potent than trovirdine, 200-times more potent than AZT, 300-times more potent than MKC-442, 400-times more potent than delavirdine, and 5000-times more potent than nevirapine against the multidrug resistant HIV-1 strain RT-MDR. HI-445 was also tested against the RT Y181C mutant A17 strain of HIV-1 and found to be >7-fold more effective than trovirdine and >1,400-fold more effective than nevirapine or delavirdine. Similarly, both HI-346 and HI-445 were more effective than trovirdine, nevirapine, and delavirdine against the problematic NNI-resistant HIV-1 strain A17-variant with both Y181C and K103N mutations in RT, although their activity was markedly reduced against this strain. Neither compound exhibited significant cytotoxicity at effective concentrations (CC50 >100 microM). These findings establish the lead compounds HI-346 and HI-445 as potent inhibitors of drug-sensitive as well as multidrug-resistant stains of HIV-1. 相似文献
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Crystal structures of Zidovudine- or Lamivudine-resistant human immunodeficiency virus type 1 reverse transcriptases containing mutations at codons 41, 184, and 215 总被引:6,自引:0,他引:6 下载免费PDF全文
Chamberlain PP Ren J Nichols CE Douglas L Lennerstrand J Larder BA Stuart DI Stammers DK 《Journal of virology》2002,76(19):10015-10019
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Uckun FM Pendergrass S Maher D Zhu D Tuel-Ahlgren L Mao C Venkatachalam TK 《Bioorganic & medicinal chemistry letters》1999,9(24):1451-3416
The thiophene-ethyl thiourea (TET) compound N′-[2-(2-thiophene)ethyl]-N′-[2-(5-bromopyridyl)]-thiourea (compound HI-443) was five times more potent than trovirdine, 1250 times more potent than nevirapine, 100 times more potent than delavirdine, 75 times more potent than MKC-442, and 50 times more potent than AZT against the multidrug resistant HIV-1 strain RT-MDR with a V106A mutation. HI-443 was almost as potent against the NNI-resistant HIV-1 strain A17 with a Y181C mutation as it was against HTLVIIIB. The activity of HI-443 against A17 was ten times more potent than that of trovirdine, 2083 times more potent than that of nevirapine, and 1042 times more potent than that of delavirdine. HI-443 inhibited the replication of the NNI-resistant HIV-1 strain A17 variant with Y181C plus K103N mutations in RT with an IC50 value of 3.3 μM, whereas the IC50 values of trovirdine, nevirapine, and delavirdine were all >100 μM. These findings establish the novel thiophene containing thiourea compound HI-443 as a novel NNI with potent antiviral activity against NNI-sensitive, NNI-resistant and multidrug-resistant strains of HIV-1. 相似文献
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Ren J Nichols C Bird L Chamberlain P Weaver K Short S Stuart DI Stammers DK 《Journal of molecular biology》2001,312(4):795-805
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