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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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Angela Corona Rita Meleddu Francesca Esposito Simona Distinto Giulia Bianco Takashi Masaoka Elias Maccioni Luis Menéndez-Arias Stefano Alcaro Stuart F. J. Le Grice Enzo Tramontano 《PloS one》2016,11(1)
The DNA polymerase and ribonuclease H (RNase H) activities of human immunodeficiency virus type 1 (HIV-1) are needed for the replication of the viral genome and are validated drug targets. However, there are no approved drugs inhibiting RNase H and the efficiency of DNA polymerase inhibitors can be diminished by the presence of drug resistance mutations. In this context, drugs inhibiting both activities could represent a significant advance towards better anti-HIV therapies. We report on the mechanisms of allosteric inhibition of a newly synthesized isatin-based compound designated as RMNC6 that showed IC50 values of 1.4 and 9.8 μM on HIV-1 RT-associated RNase H and polymerase activities, respectively. Blind docking studies predict that RMNC6 could bind two different pockets in the RT: one in the DNA polymerase domain (partially overlapping the non-nucleoside RT inhibitor [NNRTI] binding pocket), and a second one close to the RNase H active site. Enzymatic studies showed that RMNC6 interferes with efavirenz (an approved NNRTI) in its binding to the RT polymerase domain, although NNRTI resistance-associated mutations such as K103N, Y181C and Y188L had a minor impact on RT susceptibility to RMNC6. In addition, despite being naturally resistant to NNRTIs, the polymerase activity of HIV-1 group O RT was efficiently inhibited by RMNC6. The compound was also an inhibitor of the RNase H activity of wild-type HIV-1 group O RT, although we observed a 6.5-fold increase in the IC50 in comparison with the prototypic HIV-1 group M subtype B enzyme. Mutagenesis studies showed that RT RNase H domain residues Asn474 and Tyr501, and in a lesser extent Ala502 and Ala508, are critical for RMNC6 inhibition of the endonuclease activity of the RT, without affecting its DNA polymerization activity. Our results show that RMNC6 acts as a dual inhibitor with allosteric sites in the DNA polymerase and the RNase H domains of HIV-1 RT. 相似文献
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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
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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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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
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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