ABSTRACT
Novel 3-hydroxy-3-phenylpropanoate ester-azidothymidine (AZT) conjugates have been prepared using Baylis-Hillman methodology, and their potential as dual-action HIV-1 Integrase and Reverse Transcriptase inhibitors has been explored using enzyme inhibition and computer modelling techniques; their activity and HeLa cell toxicity have been compared with those of their cinnamate ester analogues.
Subject(s)
HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacology , HIV-1/drug effects , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Zidovudine/chemistry , Zidovudine/pharmacology , Anti-HIV Agents , HIV Infections/drug therapy , HIV Infections/virology , HIV Integrase/metabolism , HIV Integrase Inhibitors/chemical synthesis , HIV Reverse Transcriptase/antagonists & inhibitors , HIV Reverse Transcriptase/metabolism , HIV-1/enzymology , HeLa Cells , Humans , Molecular Docking Simulation , Reverse Transcriptase Inhibitors/chemical synthesis , Structure-Activity Relationship , Zidovudine/chemical synthesisABSTRACT
Lovastatin was identified through virtual screening as a potential inhibitor of the LEDGF/p75-HIV-1 integrase interaction. In an AlphaScreen assay, lovastatin inhibited the purified recombinant protein-protein interaction (IC50 = 1.97 ± 0.45 µm) more effectively than seven other tested statins. None of the eight statins, however, yielded antiviral activity in vitro, while only pravastatin lactone yielded detectable inhibition of HIV-1 integrase strand transfer activity (31.65% at 100 µm). A correlation between lipophilicity and increased cellular toxicity of the statins was observed.
