ИСТИНА

The integration of human immunodeficiency virus type 1 DNA into the infected cell genome is one of the crucial steps in the viral replication cycle. It is catalyzed by the viral integrase, which is thus a key potential target for new antiviral drugs. Only two integrase inhibitors, raltegravir and elvitegravir, are now approved for AIDS therapy. Unfortunately, treatment of patients with these drugs leads to the appearance of the resistant viral strains. The majority of integrase inhibitors currently at the stage of clinical trials are similar to raltegravir in terms of their mechanism of action. Raltegravir-induced cross-resistance to these compounds has already been demonstrated to develop in patients. Thus, designing new integration inhibitors that would differ from Raltegravir in terms of their mechanism of action is currently a pressing need. We have found that some methylenebisphosphonate derivatives (MBPs) inhibit integrase activity. SAR-analysis of these inhibitors allowed us identifying structural elements crucial for the inhibitory activity and understanding their mechanism of action. The inhibitory effect of MBPs is determined by the presence of chlorobenzyl substituent at the methylenebysphosphonate backbone. All the active compounds inhibit both reactions catalyzed by IN, 3’-processing and strand transfer, with comparable efficiency. The mechanism of the IN inhibition by MBPs strongly depends on the nature of the second substituent at the methylenebysphosphonate backbone; a-amino-MBP is found to be non-competitive inhibitor whereas MBPs containing other substituents inhibit IN by competitive mode. Of note, all MBP inhibitors are active against integrases with mutations providing resistance to several known IN inhibitors including raltegravir. These data lead us to conclude that these compounds show promise and need to be further studied as potential HIV-1 integrase inhibitors.