Antimalarial Activity of the Anticancer Histone Deacetylase Inhibitor SB939

Lysine Acetylation in Sexual Stage Malaria Parasites Is a Target for Antimalarial Small Molecules

“…We and others have also demonstrated that hyperacetylation of parasite histone and nonhistone proteins and global transcriptional alterations are a functional consequence of HDAC inhibitor exposure in asexual stage parasites (31,32,58,63,69,73,75). This is consistent with a mode of action of this class of compounds that targets HDAC enzymes.…”

“…Previous work from our group and others using antisera that specifically recognize acetylated forms of proteins has shown that both histone and nonhistone proteins are acetylated in asexual stage P. falciparum parasites (59,73). When we used this approach to examine protein acetylation during gametocyte development, we found that while the tetra-acetylated H4 profile was similar in all developmental stages as gametocytes matured, the panacetylated lysine profile was altered.…”

“…There are few known inhibitors of this life stage, and the only approved drug, primaquine, has significant safety concerns. Because HDAC inhibitors are also effective against asexual and exoerythrocytic parasite stages (30,73), development of a suitable drug candidate for use in combination therapies to reduce gametocyte formation could avoid many of the ethical issues associated with gametocyte-specific drugs. HDAC inhibition, either directly or indirectly via targeting of essential coregulatory proteins unique to the Plasmodium parasite, thus presents a promising strategy for the development of novel antimalarial treatments.…”

Discovery of a Selective Series of Inhibitors of Plasmodium falciparum HDACs

“…4−6 HDACs have also been identified as important regulators of transcription in P. falciparum, 7−10 and inhibition of P. falciparum histone deacetylases (Pf HDACs) has been reported to both effectively kill the parasites (Vorinostat, Figure 1) 11−16 and lead to efficacy in animal models of malaria (compound 2). 17 Such findings underscore the potential for Pf HDAC inhibitors to be used for malaria therapy. 18−20 Of the five HDAC encoding genes known in P. falciparum one has homology to mammalian class I isoforms (Pf HDAC1), two are similar class II (Pf HDAC2 and 3) mammalian HDACs, while the remaining two are class III HDACs, or silent information regulator 2 (SIR2) proteins.…”

Cancer and parasitic infections: similarities and opportunities for the development of new control tools

“…HMEs, specifically histone deacetylases (HDACs), are good antiparasitic targets; the drug suberanilohydroxamic acid (SAHA) inhibits parasite enzymatic activity. Active compounds have been developed to target the histone deacetylases of Plasmodium sp., Schistosoma mansoni, and other species 7,8 . A compound named SB939, a pan-HDAC inhibitor acting on class I, II, and IV HDACs, was found to inhibit asexual growth of Plasmodium in human erythrocytes and exoerythrocytic-stage parasites in human hepatocytes 7 .…”