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  • Furthermore the identification of the inhibitory effect of P

    2022-08-11

    Furthermore, the identification of the inhibitory effect of P. grandiflorum and ginseng extract on HDAC represents an effective workflow for gene expression similarity-based repositioning of nutraceuticals.
    Acknowledgments This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF-2017R1A5A2014768), and a grant from the Clinical Trial Center of Wonkwang University Gwangju Hospital funded by the Ministry of Health & Welfare through the Korea Health Industry Development Institute (KHIDI) (HI14C0665).
    Introduction Epigenetics has emerged as a key player in eukaryotic biological processes regulating gene expression. It is an inheritable and reversible process that affects DNA [1] and RNA [2] methylation but without any change in their sequences, post-translational modifications (PTM) on histones [3], histone variants, nucleosome positioning, and expression of non-coding RNAs [4]. Deregulations of these subtle mechanisms were initially associated with the progression of several human diseases, mainly cancers, but also ageing, neurological disorders, memory impairment, cystic fibrosis, diabetes and several other diseases. Diseases with indirect implications of epigenetics are illustrated by infections, where virus modify the epigenetic landscape for better invasiveness [5]. Beside translational applications in humans, the epigenetic regulation of gene expression is also studied in plants [6], to fight parasitic-based infections [7], and in small organisms to tailor the production of new metabolites for drug discovery programs [8]. 377 Enzymes have been identified in humans that modify the 568 by adding (writers), removing (erasers) or reading (readers) the so-called epigenetic marks, these reversible chemical modifications on histones defining the histone code. DNA is methylated by DNA Methyl Transferases (DNMT) and demethylated after methyl oxidation by Ten Eleven Translocation (TET) enzymes followed by repair mechanisms. Histones can also be methylated by lysine or arginine methyl transferases (KMT, PRMT). In addition to methylation, histones can be modified by various chemical groups such as acetylation and other types of acylation [9], sumoylation [10], ubiquitination [11], ADP-ribosylation [12], N-acetylglucosylation [13] and others. In particular, the acetylation process is regulated by the activity of two families of enzymes with antagonistic functions: histone acetyl transferases (HATs) and histone deacetylases (HDACs). HDACs, that may be called protein deacetylases (PDAC) as some of their targets are non-histone proteins, are a family of eleven zinc-dependent enzymes that have gained major interest as therapeutic targets, mainly in cancer research. Their abnormal expression in many cancer cells modifies the expression of tumour suppressor genes (TSG) and genes involved in normal cellular functions. Indeed, the treatment of cancer cells with HDAC inhibitors is an entry point for renormalization of TSG expression, leading to cancer cell apoptosis. Twenty years of synthetic efforts have led to the FDA approval of only 4 new molecules, based on HDAC inhibition, and many clinical trials have been completed or are underway with various epigenetic drug candidates, used alone or in combinations to potentiate the effects of existing drugs [14]. A fifth compound is used in clinic for years as anti-epileptic: valproic acid (VPA), a weak HDAC inhibitor frequently involved in clinical trials for its well-known clinical profile. The first compound approved was Vorinostat 1 [15] (Fig. 7, SAHA, suberoyl anilide hydroxamide), for cutaneous T-cell lymphomas, followed by romidepsin 30 [16], on the same pathology. Belinostat 2 has been approved for relapsed or refractory peripheral T-cell lymphoma [17]. Panobinostat 3 is the latest approved one for multiple myeloma [18]. HDAC inhibitors are mainly used in leukaemias and are poorly successful in solid tumours. Possible major improvements may come from a next generation of HDAC inhibitors, provided they are delivered in an optimized way [19]. The development of new generation of HDAC inhibitors is pursued and is the subject of this review. As an update of our previous 2010 review on the subject [20], we focused on new data collected from the last 5 years, including new results in mechanistic studies, novel ideas for zinc binding groups and molecular design, followed by new inhibitors synthesized worldwide. Some works also describe compounds able to inhibit HDACs and other targets at the same time, as well as those modified for detection in bioassays. Prior to these new data, some fundamentals in the epigenetic biology of HDACs need to be first recalled.