A small library of 1,3-diarylpropenones was designed and synthesized as dual inhibitors of both HIV-1 reverse transcriptase (RT) DNA polymerase (DP) and ribonuclease H (RNase H) associated functions. Compounds were assayed on these enzyme activities, which highlighted dual inhibition properties in the low-micromolar range. Interestingly, mutations in the non-nucleoside RT inhibitor binding pocket strongly affected RNase H inhibition by the propenone derivatives without decreasing their capacity to inhibit DP activity, which suggests long-range RT structural effects. Biochemical and computational studies indicated that the propenone derivatives bind two different interdependent allosteric pockets.

Design, synthesis, and biological evaluation of 1,3-diarylpropenones as dual inhibitors of HIV-1 reverse transcriptase

MELEDDU, RITA;CANNAS, VALERIA;DISTINTO, SIMONA
;
SARAIS, GIORGIA;ESPOSITO, FRANCESCA;CORONA, ANGELA;COTTIGLIA, FILIPPO;MACCIONI, ELIAS
;
TRAMONTANO, ENZO
2014-01-01

Abstract

A small library of 1,3-diarylpropenones was designed and synthesized as dual inhibitors of both HIV-1 reverse transcriptase (RT) DNA polymerase (DP) and ribonuclease H (RNase H) associated functions. Compounds were assayed on these enzyme activities, which highlighted dual inhibition properties in the low-micromolar range. Interestingly, mutations in the non-nucleoside RT inhibitor binding pocket strongly affected RNase H inhibition by the propenone derivatives without decreasing their capacity to inhibit DP activity, which suggests long-range RT structural effects. Biochemical and computational studies indicated that the propenone derivatives bind two different interdependent allosteric pockets.
antiviral agents; dual inhibitors; enzymes; HIV-1; molecular modeling; RNase H; HIV; Reverse transcriptase; Dual inhibitors; Ribonuclease H
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11584/55058
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