共查询到20条相似文献,搜索用时 31 毫秒
1.
Taylor DL Ahmed PS Tyms AS Wood LJ Kelly LA Chambers P Clarke J Bedard J Bowlin TL Rando RF 《Antiviral chemistry & chemotherapy》2000,11(4):291-301
The heterosubstituted nucleoside analogue dOTC [( )-2'-deoxy-3'-oxa-4'-thiocytidine, BCH-10652] is a racemic compound structurally related to 3TC (lamivudine), but has the oxygen and sulphur in the furanosyl ring transposed. Both the enantiomers (-)dOTC (BCH-10618) and (+)dOTC (BCH-10619) had equivalent activity against wild-type strains of HIV-1 in C8166 T-cells (EC50 1.0-10.0 microM) and in PBMCs (EC50 0.1-3.0 microM). Investigation of the activity of dOTC and its enantiomers against laboratory strains of HIV-1 with defined resistance to 3TC, AZT (zidovudine), ddl (didanosine), PMEA (adefovir), nevirapine and saquinavir indicated that sensitivity was maintained (<3-fold change in EC50) in all cases, with the exception of HIV-1RF 3TC-resistant viruses. The degree of resistance recorded for dOTC (four- to sevenfold), (-)dOTC (five- to eightfold) and (+)dOTC (five- to >18-fold) against these M1841 or M184V mutants, was significantly less than that recorded for 3TC (>100-fold). In addition, the inhibitory effect of the compounds against clinical isolates of HIV-1 recovered from patients with suspected resistance to 3TC and AZT was investigated. Clinical isolates were genotyped using the Murex Line Probe Assay (LiPA) and subgrouped into wild-type, 3TC-resistant and dual 3TC/AZT-resistant, as well as undefined or mixed genotype populations. Compared with the mean EC50 values obtained with genotypically and phenotypically wild-type clinical isolates, the mean EC50 values calculated for isolates phenotypically resistant to 3TC or 3TC and AZT were only 2.6-, 1.6- and 8.2-fold higher for dOTC, (-)dOTC and (+)dOTC, respectively. When the rate of emergence of virus resistant to dOTC and its enantiomers in vitro was investigated, virus resistant to (+)dOTC was readily selected for (<10 passages), and a methionine (ATG) to isoleucine (ATA) amino acid change at codon 184 was identified. In contrast, virus resistant to dOTC and (-)dOTC took longer to appear (15-20 passages), with a methionine (ATG) to valine (GTG) amino acid change at position 184 identified in both cases. In addition, virus passaged 20 times in the presence of dOTC also had a partial lysine (AAA) to arginine (AGA) exchange at position 65. These viruses showed only low-level resistance to dOTC and its enantiomers, but were highly resistant to 3TC. The antiviral effects of dOTC in combination with the nucleoside RT inhibitors AZT, 3TC, d4T (stavudine) and ddl, the non-nucleoside RT inhibitor nevirapine and the protease inhibitors saquinavir, ritonavir and indinavir was investigated. Two-way drug combination assays were carried out in peripheral blood mononuclear cell (PBMC) cultures by measuring the reduction in p24 viral antigen levels, and data was analysed using the MacSynergy II program. dOTC in combination with 3TC or d4T showed a moderate synergistic effect while all other combinations had an additive interaction. 相似文献
2.
Mechanism of Action and In Vitro Activity of 1′,3′-Dioxolanylpurine Nucleoside Analogues against Sensitive and Drug-Resistant Human Immunodeficiency Virus Type 1 Variants
下载免费PDF全文
![点击此处可从《Antimicrobial agents and chemotherapy》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Zhengxian Gu Mark A. Wainberg Nghe Nguyen-Ba Lucille LHeureux Jean-Marc de Muys Terry L. Bowlin Robert F. Rando 《Antimicrobial agents and chemotherapy》1999,43(10):2376-2382
3.
4.
5.
6.
Activity against human immunodeficiency virus type 1, intracellular metabolism, and effects on human DNA polymerases of 4'-ethynyl-2-fluoro-2'-deoxyadenosine
下载免费PDF全文
![点击此处可从《Antimicrobial agents and chemotherapy》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Nakata H Amano M Koh Y Kodama E Yang G Bailey CM Kohgo S Hayakawa H Matsuoka M Anderson KS Cheng YC Mitsuya H 《Antimicrobial agents and chemotherapy》2007,51(8):2701-2708
7.
Anti-human immunodeficiency virus type 1 activity and in vitro toxicity of 2''-deoxy-3''-thiacytidine (BCH-189), a novel heterocyclic nucleoside analog. 总被引:2,自引:13,他引:2
下载免费PDF全文
![点击此处可从《Antimicrobial agents and chemotherapy》网站下载免费的PDF全文](/ch/ext_images/free.gif)
H Soudeyns X I Yao Q Gao B Belleau J L Kraus N Nguyen-Ba B Spira M A Wainberg 《Antimicrobial agents and chemotherapy》1991,35(7):1386-1390
We describe a novel nucleoside analog, 2'-deoxy-3'-thiacytidine (BCH-189), in which the 3' carbon of the ribose ring of 2'-deoxycytidine has been replaced by a sulfur atom. In MT-4 T cells, this compound had significant time- and dose-dependent antiviral activity against five different strains of human immunodeficiency virus type 1 (HIV-1) (mean 50% inhibitory dose, 0.73 microM); known 3'-azido-3'-deoxythymidine (AZT)-resistant HIV-1 variants did not exhibit cross-resistance to it. BCH-189 also suppressed HIV-1 replication in the U937 monocytoid cell line as well as in primary cultures of human peripheral blood mononuclear cells; in these latter systems, suppression was fuller and longer lasting than that induced by AZT. Moreover, BCH-189 was less toxic than AZT in cell culture. BCH-189 may be a promising drug for the treatment of HIV-1-associated disease. 相似文献
8.
Differential maintenance of the M184V substitution in the reverse transcriptase of human immunodeficiency virus type 1 by various nucleoside antiretroviral agents in tissue culture
下载免费PDF全文
![点击此处可从《Antimicrobial agents and chemotherapy》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Petrella M Oliveira M Moisi D Detorio M Brenner BG Wainberg MA 《Antimicrobial agents and chemotherapy》2004,48(11):4189-4194
9.
10.
Synergistic inhibition of human immunodeficiency virus type 1 replication in vitro by two-drug and three-drug combinations of 3''-azido-3''-deoxythymidine, phosphonoformate, and 2'',3''-dideoxythymidine.
下载免费PDF全文
![点击此处可从《Antimicrobial agents and chemotherapy》网站下载免费的PDF全文](/ch/ext_images/free.gif)
X B Kong Q Y Zhu R M Ruprecht K A Watanabe J M Zeidler J W Gold B Polsky D Armstrong T C Chou 《Antimicrobial agents and chemotherapy》1991,35(10):2003-2011
11.
12.
In vitro selection of mutations in the human immunodeficiency virus type 1 reverse transcriptase that decrease susceptibility to (-)-beta-D-dioxolane-guanosine and suppress resistance to 3'-azido-3'-deoxythymidine
下载免费PDF全文
![点击此处可从《Antimicrobial agents and chemotherapy》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Bazmi HZ Hammond JL Cavalcanti SC Chu CK Schinazi RF Mellors JW 《Antimicrobial agents and chemotherapy》2000,44(7):1783-1788
13.
14.
15.
Genotypic and phenotypic resistance patterns of human immunodeficiency virus type 1 variants with insertions or deletions in the reverse transcriptase (RT): multicenter study of patients treated with RT inhibitors
下载免费PDF全文
![点击此处可从《Antimicrobial agents and chemotherapy》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Masquelier B Race E Tamalet C Descamps D Izopet J Buffet-Janvresse C Ruffault A Mohammed AS Cottalorda J Schmuck A Calvez V Dam E Fleury H Brun-Vézinet F;ANRS AC Resistance study group. French Agence Nationale de Recherches sur le SIDA 《Antimicrobial agents and chemotherapy》2001,45(6):1836-1842
16.
17.
Differential removal of thymidine nucleotide analogues from blocked DNA chains by human immunodeficiency virus reverse transcriptase in the presence of physiological concentrations of 2'-deoxynucleoside triphosphates
下载免费PDF全文
![点击此处可从《Antimicrobial agents and chemotherapy》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Meyer PR Matsuura SE Schinazi RF So AG Scott WA 《Antimicrobial agents and chemotherapy》2000,44(12):3465-3472
18.
19.
20.
William E. Delaney IV Thomas G. Miller Harriet C. Isom 《Antimicrobial agents and chemotherapy》1999,43(8):2017-2026