Histone Deacetylases Play a Major Role in the Transcriptional Regulation of the Plasmodium falciparum Life Cycle

The apparent paucity of molecular factors of transcriptional control in the genomes of Plasmodium parasites raises many questions about the mechanisms of life cycle regulation in these malaria parasites. Epigenetic regulation has been suggested to play a major role in the stage specific gene expression during the Plasmodium life cycle. To address some of these questions, we analyzed global transcriptional responses of Plasmodium falciparum to a potent inhibitor of histone deacetylase activities (HDAC). The inhibitor apicidin induced profound transcriptional changes in multiple stages of the P. falciparum intraerythrocytic developmental cycle (IDC) that were characterized by rapid activation and repression of a large percentage of the genome. A major component of this response was induction of genes that are otherwise suppressed during that particular stage of the IDC or specific for the exo-erythrocytic stages. In the schizont stage, apicidin induced hyperacetylation of histone lysine residues H3K9, H4K8 and the tetra-acetyl H4 (H4Ac4) and demethylation of H3K4me3. Interestingly, we observed overlapping patterns of chromosomal distributions between H4K8Ac and H3K4me3 and between H3K9Ac and H4Ac4. There was a significant but partial association between the apicidin-induced gene expression and histone modifications, which included a number of stage specific transcription factors. Taken together, inhibition of HDAC activities leads to dramatic de-regulation of the IDC transcriptional cascade, which is a result of both disruption of histone modifications and up-regulation of stage specific transcription factors. These findings suggest an important role of histone modification and chromatin remodeling in transcriptional regulation of the Plasmodium life cycle. This also emphasizes the potential of P. falciparum HDACs as drug targets for malaria chemotherapy

Structure elucidation and antimalarial activity of apicidin F : an apicidin-like compound produced by Fusarium fujikuroi

Apicidins are cyclic tetrapeptides with histone deacetylase inhibitory activity. Since their discovery in 1996 a multitude of studies concerning the activity against protozoa and certain cancer cell lines of natural and synthetic apicidin analogues have been published. Until now, the only published natural sources of apicidin are the fungus Fusarium pallidoroseum, later known as F. semitectum and two unspecified Fusarium strains. The biosynthetic origin of apicidins could be associated with a gene cluster, and a biosynthetic pathway has been proposed. Recently, our group was able to identify for the first time an apicidin-like gene cluster in F. fujikuroi that apparently does not lead to the production of any known apicidin analogue. By overexpressing the pathway-specific transcription factor we were able to identify a new apicidin-like compound. The present study provides the complete structure elucidation of the new compound, named apicidin F. Activity evaluation against Plasmodium falciparum showed good in vitro activity with an IC50 value of 0.67 μM

Difficult macrocyclizations: New strategies for synthesizing highly strained cyclic tetrapeptides

Cyclic tetrapeptides are an intriguing class of natural products. To synthesize highly strained cyclic tetrapeptides; we developed a macrocyclization strategy that involves the inclusion of 2-hydroxy-6-nitrobenzyl (HnB) group at the N-terminus and in the middle of the sequence. The N-terminal auxiliary performs a ring closure/ring contraction role, and the backbone auxiliary promotes cis amide bonds to facilitate the otherwise difficult ring contraction. Following this route, the all-L cyclic tetrapeptide cyclo-[Tyr-Arg-Phe-Ala] was successfully prepared