In the continuous effort to identify new HIV-1 inhibitors endowed with innovative mechanisms, the dual inhibition of different viral functions would provide a significant advantage against drug resistant variants. The HIV-1 reverse transcriptase (RT) associated Ribonuclease H (RNase H) is the only viral encoded enzymatic activity that still lacks an efficient inhibitor. We synthesized a library of 3,5-diamino-N-aryl-1H-pyrazole-4-carbothioamide and 4-amino-5-benzoyl-N-phenyl-2-(substituted-amino)-1H-pyrrole-3-carbothioamide derivatives and tested them against RNase H activity. We identified the pyrazolecarbothioamide derivative A15, able to inhibit viral replication and both RNase H and RNA-dependent DNA polymerase (RDDP) RT-associated activities in the low micromolar range. Docking simulations hypothesized its binding to two RT pockets. Site directed mutagenesis experiments showed that, with respect to wt RT, V108A substitution strongly reduced A15 IC50 values (12.6 fold for RNase H inhibition and 4.7 fold for RDDP), while substitution A502F caused a 9.0 fold increase in its IC50 value for RNase H, not affecting the RDDP inhibition, reinforcing the hypothesis of a dual site-inhibition. Moreover, A15 retained good inhibition potency against three non-nucleoside RT inhibitor (NNRTI) resistant enzymes, confirming a mode of action unrelated to NNRTIs and suggesting its potential as a lead compound for development of new HIV-1 RT dual inhibitors active against drug resistant viruses.

Design, synthesis and antiviral evaluation of novel heteroarylcarbothioamide derivatives as dual inhibitors of HIV-1 Reverse transcriptase-associated RNase H and RDDP functions

CORONA, ANGELA;ONNIS, VALENTINA;DEPLANO, ALESSANDRO;BIANCO, GIULIA;DEMURTAS, MONICA;DISTINTO, SIMONA;ESPOSITO, FRANCESCA;TRAMONTANO, ENZO
2017-01-01

Abstract

In the continuous effort to identify new HIV-1 inhibitors endowed with innovative mechanisms, the dual inhibition of different viral functions would provide a significant advantage against drug resistant variants. The HIV-1 reverse transcriptase (RT) associated Ribonuclease H (RNase H) is the only viral encoded enzymatic activity that still lacks an efficient inhibitor. We synthesized a library of 3,5-diamino-N-aryl-1H-pyrazole-4-carbothioamide and 4-amino-5-benzoyl-N-phenyl-2-(substituted-amino)-1H-pyrrole-3-carbothioamide derivatives and tested them against RNase H activity. We identified the pyrazolecarbothioamide derivative A15, able to inhibit viral replication and both RNase H and RNA-dependent DNA polymerase (RDDP) RT-associated activities in the low micromolar range. Docking simulations hypothesized its binding to two RT pockets. Site directed mutagenesis experiments showed that, with respect to wt RT, V108A substitution strongly reduced A15 IC50 values (12.6 fold for RNase H inhibition and 4.7 fold for RDDP), while substitution A502F caused a 9.0 fold increase in its IC50 value for RNase H, not affecting the RDDP inhibition, reinforcing the hypothesis of a dual site-inhibition. Moreover, A15 retained good inhibition potency against three non-nucleoside RT inhibitor (NNRTI) resistant enzymes, confirming a mode of action unrelated to NNRTIs and suggesting its potential as a lead compound for development of new HIV-1 RT dual inhibitors active against drug resistant viruses.
HIV-1 therapeutic agents; RT dual inhibitors; HIV-1 Ribonuclease H; Heteroarylcarbothioamide
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11584/218196
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