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 discussed
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 discussed
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