Mutagenic study on HIV-1 reverse transcriptase to explore the mechanism of action of HIV-1 reverse transcriptase dual inhibitors
CORONA, ANGELA;Meleddu R.;ESPOSITO, FRANCESCA;DISTINTO, SIMONA;MACCIONI, ELIAS;TRAMONTANO, ENZO
2012-01-01
Abstract
Background. The HIV-1 RT has two associated activities: i) the DNA polymerase activity (both RNA and DNA dependent) and ii) the ribonuclease H (RNase H) activity, that selectively degrades the RNA strand of the RNA/DNA hybrid formed during the reverse transcription process. The HIV-1 RT-associated RNase H function is one of the several steps of the HIV-1 life cycle that are potentially vulnerable to a specific inhibition. Several studies have demonstrated that the abolition of the HIV-1 RNase H function stops the virus replication. All RT inhibitors currently approved for the treatment of HIV infection inhibit the RT polymerase activity, while none of them block the RT associated RNase H activity. Until now, only a few compounds have been reported to inhibit the HIV-1 RNase H function. However, with very few exceptions, they are not truly selective for the HIV-1 RT-associated RNase H activity since most of them inhibit also the HIV-1 RT-associated RDDP activity or the RNase H from other organisms. Since several years we have been engaged in the design and synthesis of RNase H inhibitors. Methods. Recently, we have discovered a new class of RNase H selective inhibitors characterized by quinolonyl carboxylic acid and 5,6-dihydroxybenzopyranone scaffolds and tested them on the HIV-1 RT-associated RNase H function. Results. The preliminary data showed that newly synthesized compounds inhibited the HIV-1 RT-associated RNase H function in the low micromolar range. Conclusions. SAR analysis and mode of action of the inhibitors will be discussedItems in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.