Structural isomers of cinnamic hydroxamic acids block HCV replication via different mechanisms
Maxim V Kozlov1, Konstantin A Konduktorov1, Alsu Z Malikova1
1Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova 32, Moscow, 119991, Russia.
European Journal of Medicinal Chemistry
|September 27, 2019
Summary
Researchers synthesized cinnamic hydroxamic acids (CHAs) and found they inhibit hepatitis C virus (HCV) replication by targeting histone deacetylases (HDACs). Para-substituted CHAs showed stronger antiviral activity, suggesting additional cellular targets beyond HDACs.
Area of Science:
- Medicinal Chemistry
- Virology
- Biochemistry
Background:
- Hepatitis C virus (HCV) infection is a major global health concern.
- Histone deacetylases (HDACs) are implicated in viral replication.
- Cinnamic hydroxamic acids (CHAs) are a class of compounds with potential biological activity.
Purpose of the Study:
- To synthesize and evaluate a series of ortho-, meta-, and para-substituted cinnamic hydroxamic acids (CHAs) for anti-HCV activity.
- To investigate the relationship between CHA structure, HDAC inhibition, and HCV replicon suppression.
- To identify potential novel cellular targets for anti-HCV drug development.
Main Methods:
- Synthesis of ortho-, meta-, and para-substituted CHAs with varying linker lengths.
- HCV replicon cell-based assay to measure antiviral activity.
- Enzyme inhibition assays to determine the effect of CHAs on different HDAC classes (I, IIb).
Main Results:
- Anti-HCV activity was observed for synthesized CHAs, correlating with HDAC inhibition.
- Ortho-CHAs showed activity linked to HDAC8 inhibition.
- Meta-CHAs correlated with inhibition of HDAC1/2/3 and HDAC6.
- Para-CHAs exhibited significantly higher antiviral potency than meta-CHAs, despite similar HDAC inhibition profiles, suggesting additional targets.
Conclusions:
- Cinnamic hydroxamic acids demonstrate potent anti-HCV activity through dual mechanisms, including HDAC inhibition.
- Structural isomerism (ortho-, meta-, para-) significantly impacts anti-HCV efficacy and target engagement.
- The enhanced activity of para-CHAs points to unexplored cellular targets crucial for HCV replication, warranting further investigation.
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