Abstract
The structures of the catalytic core of two HIV-1 encoded enzymes play a crucial role in the retroviral cycle: integrase and RNase H exhibit striking similarities. These enzymes also share a similar mechanism of catalysis. The homologies between RNase H and integrase led to studying the effect of the RNase H inhibitors on integrase. ODNs aptamers active on RNase H were shown to be strong IN inhibitors. On the contrary, compounds from the diketo acid family were previously known as integrase inhibitors. One compound of this family is able to inhibit the RNase H activity, but has no effect on integrase. Cellular topoisomerase 1 also shares a mechanism similar to that of HIV-1 integrase and RNase H. It has been reported to be present in retroviral particles and to enhance cDNA synthesis. Some topoisomerase inhibitors have been shown to be active on integrase. Moreover, topoisomerase, integrase and RNase H are inhibited by G-rich oligonucleotides. A G-quartet structure is necessary for integrase, but not for topoisomerase inhibition. This suggests that prototype structures can be exploited to develop inhibitors of two related enzymes, such as the RNase H and integrase activities of HIV-1 RT.
Keywords: hiv-1 replication, polynucleotidyltransferase family, integrase, rnase h, topoisomerase, cross-inhibition
Current Pharmaceutical Design
Title: Closely Related Antiretroviral Agents as Inhibitors of Two HIV-1 Enzymes, Ribonuclease H and Integrase: “Killing Two Birds with One Stone”
Volume: 10 Issue: 30
Author(s): Marie-Line Andreola
Affiliation:
Keywords: hiv-1 replication, polynucleotidyltransferase family, integrase, rnase h, topoisomerase, cross-inhibition
Abstract: The structures of the catalytic core of two HIV-1 encoded enzymes play a crucial role in the retroviral cycle: integrase and RNase H exhibit striking similarities. These enzymes also share a similar mechanism of catalysis. The homologies between RNase H and integrase led to studying the effect of the RNase H inhibitors on integrase. ODNs aptamers active on RNase H were shown to be strong IN inhibitors. On the contrary, compounds from the diketo acid family were previously known as integrase inhibitors. One compound of this family is able to inhibit the RNase H activity, but has no effect on integrase. Cellular topoisomerase 1 also shares a mechanism similar to that of HIV-1 integrase and RNase H. It has been reported to be present in retroviral particles and to enhance cDNA synthesis. Some topoisomerase inhibitors have been shown to be active on integrase. Moreover, topoisomerase, integrase and RNase H are inhibited by G-rich oligonucleotides. A G-quartet structure is necessary for integrase, but not for topoisomerase inhibition. This suggests that prototype structures can be exploited to develop inhibitors of two related enzymes, such as the RNase H and integrase activities of HIV-1 RT.
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Cite this article as:
Andreola Marie-Line, Closely Related Antiretroviral Agents as Inhibitors of Two HIV-1 Enzymes, Ribonuclease H and Integrase: “Killing Two Birds with One Stone”, Current Pharmaceutical Design 2004; 10 (30) . https://dx.doi.org/10.2174/1381612043382648
DOI https://dx.doi.org/10.2174/1381612043382648 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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