Design, synthesis, and biological evaluation of 1,3-diarylpropenones as dual inhibitors of HIV-1 reverse transcriptase.
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.
Department of Life and Environmental Sciences, University of Cagliari, Via Ospedale 72, 09124 Cagliari (Italy).
Rita
R
Meleddu
Valeria
V
Cannas
Simona
S
Distinto
Giorgia
G
Sarais
Claudia
C
Del Vecchio
Francesca
F
Esposito
Giulia
G
Bianco
Angela
A
Corona
Filippo
F
Cottiglia
Stefano
S
Alcaro
Cristina
C
Parolin
Anna
A
Artese
Daniela
D
Scalise
Massimo
M
Fresta
Antonella
A
Arridu
Francesco
F
Ortuso
Elias
E
Maccioni
Enzo
E
Tramontano
D000475:Alkenes / Q000138:chemical synthesis / Q000737:chemistry; D001665:Binding Sites; D015195:Drug Design; D057809:HEK293 Cells; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D016914:Ribonuclease H / Q000037:antagonists & inhibitors / Q000378:metabolism
D000475:Alkenes; D018894:Reverse Transcriptase Inhibitors; C013658:propylene; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D016914:Ribonuclease H
HIV-1; RNase H; antiviral agents; dual inhibitors; enzymes; molecular modeling