HIV-1 integrase (IN) and Ribonuclease H (RNase) H belong to a polynucleotidyl trasferases class and share structural similarities among which the coordination of two Mg2+ ions in their active sites required to catalyze their reactions. Several compounds initially developed as HIV-1 IN inhibitors have been also screened against HIV-1 reverse transcriptase associated RNase H function. Among them, diketo acid (DKA) derivatives are able to chelate divalent metal ions present in the active site of IN and are capable to inhibit also the HIV-1 RNase H function. The simultaneous inhibition of both HIV-1 IN and RNase H activities is an innovative approach to develop dual inhibitors. We have reported that DKA derivative RDS 1643 inhibit the HIV-1 RNase H activity with IC50 value of 13 μM and it slightly inhibited the HIV-1 IN reaction (IC50 value of 92-98 μM). Moreover, in cell-based assays it was able to block the replication of wild type HIV-1, showing an EC50 value of 13 μM and a CC50 value of 63 μM. We have synthesized and tested a series of RDS1643 derivatives against both HIV-1 IN and RNase H RT-associated functions and the results shown that a series compounds are dual inhibitors with an IC50 value between 0.042 and 10 µM.
HIV-1 Integrase and Ribonuclease H inhibition by pyrrolyl diketohexenoic acids derivatives
ESPOSITO, FRANCESCA;TRAMONTANO, ENZO
2012-01-01
Abstract
HIV-1 integrase (IN) and Ribonuclease H (RNase) H belong to a polynucleotidyl trasferases class and share structural similarities among which the coordination of two Mg2+ ions in their active sites required to catalyze their reactions. Several compounds initially developed as HIV-1 IN inhibitors have been also screened against HIV-1 reverse transcriptase associated RNase H function. Among them, diketo acid (DKA) derivatives are able to chelate divalent metal ions present in the active site of IN and are capable to inhibit also the HIV-1 RNase H function. The simultaneous inhibition of both HIV-1 IN and RNase H activities is an innovative approach to develop dual inhibitors. We have reported that DKA derivative RDS 1643 inhibit the HIV-1 RNase H activity with IC50 value of 13 μM and it slightly inhibited the HIV-1 IN reaction (IC50 value of 92-98 μM). Moreover, in cell-based assays it was able to block the replication of wild type HIV-1, showing an EC50 value of 13 μM and a CC50 value of 63 μM. We have synthesized and tested a series of RDS1643 derivatives against both HIV-1 IN and RNase H RT-associated functions and the results shown that a series compounds are dual inhibitors with an IC50 value between 0.042 and 10 µM.
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