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Genotypic correlates of phenotypic resistance to efavirenz in virus isolates from patients failing nonnucleoside reverse transcriptase inhibitor therapy 总被引:6,自引:0,他引:6 下载免费PDF全文
Bacheler L Jeffrey S Hanna G D'Aquila R Wallace L Logue K Cordova B Hertogs K Larder B Buckery R Baker D Gallagher K Scarnati H Tritch R Rizzo C 《Journal of virology》2001,75(11):4999-5008
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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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Ambrose Z Boltz V Palmer S Coffin JM Hughes SH Kewalramani VN 《Journal of virology》2004,78(24):13553-13561
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Reduced susceptibility of human immunodeficiency virus type 1 (HIV-1) from patients with primary HIV infection to nonnucleoside reverse transcriptase inhibitors is associated with variation at novel amino acid sites 下载免费PDF全文
Brown AJ Precious HM Whitcomb JM Wong JK Quigg M Huang W Daar ES D'Aquila RT Keiser PH Connick E Hellmann NS Petropoulos CJ Richman DD Little SJ 《Journal of virology》2000,74(22):10269-10273
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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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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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Venkatachalam TK Sudbeck EA Mao C Uckun FM 《Bioorganic & medicinal chemistry letters》2001,11(4):523-528