Potent Antimalarial Activity of Histone Deacetylase Inhibitor Analogues

Abstract

The malaria parasite Plasmodium falciparum has at least five putative histone deacetylase (HDAC) enzymes, which have been proposed as new antimalarial drug targets and may play roles in regulating gene transcription, like the better-known and more intensively studied human HDACs (hHDACs). Fourteen new compounds derived from L-cysteine or 2-aminosuberic acid were designed to inhibit P. falciparum HDAC-1 (PfHDAC-1) based on homology modeling with human class I and class II HDAC enzymes. The compounds displayed highly potent antiproliferative activity against drug-resistant (Dd2) or drug sensitive (3D7) strains of P. falciparum in vitro (50% inhibitory concentration of 13 to 334 nM). Unlike known hHDAC inhibitors, some of these new compounds were significantly more toxic to P. falciparum parasites than to mammalian cells. The compounds inhibited P. falciparum growth in erythrocytes at both the early and late stages of the parasite's life cycle and caused altered histone acetylation patterns (hyperacetylation), which is a marker of HDAC inhibition in mammalian cells. These results support PfHDAC enzymes as being promising targets for new antimalarial drugs.

Direct effects of non-antifungal agents used in cancer chemotherapy and organ transplantation on the development and virulence ofCandidaandAspergillusspecies

“…14,110,111 As HDACis potentiate the cytotoxicity of DNA methylation inhibitors (e.g., cisplatin, the anthracyclines, dexamethasone), they may be used together with these inhibitors. [109][110][111] Mammalian and fungal HDACs are substantially homologous and investigators have identified several classes and subclasses of HDACs in fungi (e.g., the class I enzymes RpdA and HosA, the class II enzymes HdaA and HosB). 112 Amongst proteins within the HDAC complex, H3K56ac has a key role in the DNA damage response; this protein may be fungal-specific.…”

“…HDACis exhibit promise in the treatment of cancer and certain parasitic and viral infections. 14,109 The HDACis include trichostatin A (TSA), romidepsin/depsipeptide, suberoylanilide hydroxamic acid (SAHA; vorinostat), panobinostat and MG-CD0103 (mocetinostat). However, only SAHA and romidepsin are licensed for clinical use (for cutaneous T cell lymphoma).…”

Chromatin regulation in schistosomes and histone modifying enzymes as drug targets

“…In the case of P. falciparum, it was possible to develop HDACi that are significantly more toxic to the parasite than toward human cells (Andrews et al 2008, Wheatley et al 2010. We have shown (Dubois et al 2009) that HDACi such as trichostatin A (TSA) and valproic acid (VPA) cause the death of S. mansoni larvae and adult worms in vitro and that this is probably via the induction of apoptosis in the parasites (see below).…”

“…HDACi have also stimulated interest as anti-parasitic drugs and have been tested against P. falciparum (Andrews et al 2000(Andrews et al , 2008, Toxoplasma gondii (Strobl et al 2007) and the major kinetoplastid parasites (Mai et al 2004, Horn 2008. In the case of P. falciparum, it was possible to develop HDACi that are significantly more toxic to the parasite than toward human cells (Andrews et al 2008, Wheatley et al 2010.…”

“…Subsequent work showed that TSA was also active in vitro and that suberic acid bisdimethylamide had a cytostatic effect on the murine malaria parasite Plasmodium berghei in vivo (Andrews et al 2000). Subsequently, compounds derived from L-cysteine or 2-aminosuberic acid were designed to inhibit P. falciparum HDAC-1 based on homology modelling with human class I and class II HDAC enzymes (Andrews et al 2008). These compounds showed a high antiproliferative activity in the nM range and some were much more toxic toward the parasites than toward mammalian cells.…”