Repurposing of HDAC inhibitors towards anti-HCV drug discovery: how to teach old dog new tricks?
"the most fruitful basis of the discovery of a new drug is to start with an old drug”, “...the anti-HCV activities of HDAC inhibitors provide evidence for the potential of them in the treatment of HCV infections."
Currently, drugs targeted viral proteins of HCV lifecycle (NS3/4A protease, NS5B polymerase and NS5A protein) are available. However, there is still a great necessity in developing new classes of pan-genotypic antiviral agents with high genetic barrier to the development of resistance and tolerability in treating HCV infection. The lysine (de)acetylation state of cellular proteins regulated by the histone acetyl transferases and histone deacetylases (HDACs) is extensively investigated among the epigenetic mechanisms. HDACs have emerged as a prominent post-translational modification of a wide range of proteins and are involved in the regulation of numerous genes, which are closely involved in HCV infection. Recent studies afford a pharmacological validation of the requirement for HDAC in the regulation of HCV replication. Recent studies indicated that some histone deacetylase (HDAC) inhibitors exhibited potent and selective anti-HCV activity. HDAC multipotent inhibitor, suberoylanilide hydroxamic acid (SAHA), has suppressive effect on HCV replication. Selective HDAC6 inhibitors, benzohydroxamic acid derivatives (BHAs) and pyridine hydroxamic acids (PHAs) can significantly affect the propagation of HCV. The cinnamic hydroxamic acids and benzo[b]thiophen-2-hydroxamic acids show potent anti-HCV activity. These hydroxamic acid-based anti-HCV agents would provide some implications in elucidating the mechanism of action. Therefore, it is a promising starting point for further structural optimization and mechanistic studies.
personal research page: http://www.pharm.sdu.edu.cn/a/english/Professors/1...
Zhao F, Liu N, Zhan P, Liu X. Repurposing of HDAC inhibitors towards anti-HCV drug discovery: how to teach old dog new tricks? Future Med. Chem. doi:
10.4155/FMC.15.76 (in press).