Apicidin: A novel antiprotozoal agent that inhibits parasite histone deacetylase

Abstract

A novel fungal metabolite, apicidin [cyclo(N-O-methyl-L-tryptophanyl-L-isoleucinyl-D-pipecolinyl-L-2-amino-8-oxodecanoyl)], that exhibits potent, broad spectrum antiprotozoal activity in vitro against Apicomplexan parasites has been identified. It is also orally and parenterally active in vivo against Plasmodium berghei malaria in mice. Many Apicomplexan parasites cause serious, life-threatening human and animal diseases, such as malaria, cryptosporidiosis, toxoplasmosis, and coccidiosis, and new therapeutic agents are urgently needed. Apicidin's antiparasitic activity appears to be due to low nanomolar inhibition of Apicomplexan histone deacetylase (HDA), which induces hyperacetylation of histones in treated parasites. The acetylation-deacetylation of histones is a thought to play a central role in transcriptional control in eukaryotic cells. Other known HDA inhibitors were also evaluated and found to possess antiparasitic activity, suggesting that HDA is an attractive target for the development of novel antiparasitic agents.

Small-molecule histone methyltransferase inhibitors display rapid antimalarial activity against all blood stage forms inPlasmodium falciparum

“…injection, but required multiple doses over several days beginning immediately after parasite infection (27). The HDAC inhibitor apicidin revealed similar activity in vivo, but without a total cure (25). In comparison with other epigenetic targeting studies reporting in vivo effects, our results suggest considerable promise in targeting parasite histone methyltransferases using BIX-01294 derivatives.…”

“…Aberrant histone methylation has been associated with a variety of human cancers, and as such protein methyltransferases are a current target class for the development for new cancer chemotherapies (20,21). As for targeting parasite epigenetic gene regulation through histone posttranslational modifications, the few studies present in the literature have focused exclusively on modulating histone acetylation via the histone acetyltransferase (HAT) inhibitors curcumin (22) or anacardic acid (23) or the histone deacetylase (HDAC) inhibitors nicotinamide (24), apicidin (25), or derivatives of hydroxamic acid (26)(27)(28). Although the characterization of P. falciparum protein arginine N-methyltransferase (PRMT1) activity and inhibition has been described (29), there are no reports of drug discovery efforts targeting the parasite histone lysine methyltransferases (HKMTs).…”

Toxoplasma gondiigene expression is under the control of regulatory pathways acting through chromatin structure

“…HDACi are now emerging as an interesting new class of antiprotozoal agent. Indeed, apicidin, a fungal metabolite, has broad-spectrum activity against the apicomplexan parasites, presumably via inhibition of protozoan histone deacetylases, and demonstrates efficacy against Plasmodium berghei malaria in mice (Darkin-Rattray et al, 1996). The use of different class of HDACi is valuable to study the cause-and-effect relationship between histone acetylation and gene activity in T. gondii.…”

Regulation of cyclic peptide biosynthesis in a plant pathogenic fungus by a novel transcription factor

“…HC-toxin, like other Aeo-containing cyclic tetrapeptides such as trapoxin (7), is a potent inhibitor of histone deacetylases from maize and other organisms (8,9). By a mechanism that remains to be elucidated, inhibition of histone deacetylase during the early stages of infection permits C. carbonum to infect and colonize maize plants (10).…”