Apicidin: a novel antiprotozoal agent that inhibits parasite histone deacetylase.

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.

[1]  S. Tamura,et al.  Structure of Cyl-2, a Novel Cyclotetrapeptide from Cylindrocladium scoparium , 1973 .

[2]  A. Mahowald,et al.  Histones of Drosophila embryos. Electrophoretic isolation and structural studies. , 1974, The Journal of biological chemistry.

[3]  R. Huguenin,et al.  Isolierung und Strukturaufklärung von Chlamydocin , 1974 .

[4]  W. Trager,et al.  Human malaria parasites in continuous culture. , 1976, Science.

[5]  V. Ingram,et al.  n-Butyrate causes histone modification in HeLa and Friend erythroleukaemia cells , 1977, Nature.

[6]  J. Méry,et al.  Enzymatic deacetylation of a synthetic peptide fragment of histone H4 , 1979, FEBS letters.

[7]  C. Sweeley,et al.  Structure of HC-toxin, a cyclic tetrapeptide from helminthosporium carbonum , 1982 .

[8]  K. Nakahara,et al.  Studies on WF-3161, a new antitumor antibiotic. , 1983, The Journal of antibiotics.

[9]  D. Schmatz,et al.  Purification of Eimeria sporozoites by DE-52 anion exchange chromatography. , 1984, The Journal of protozoology.

[10]  D. Schmatz,et al.  Eimeria tenella: parasite-specific incorporation of 3H-uracil as a quantitative measure of intracellular development. , 1986, The Journal of protozoology.

[11]  D. Lindsay,et al.  Complete development of Caryospora bigenetica (Apicomplexa: Eimeriidae) in vitro. , 1988, The Journal of protozoology.

[12]  L. H. Cohen,et al.  [25] Analysis of histone subtypes and their modified forms by polyacrylamide gel electrophoresis , 1989 .

[13]  J. Dubey,et al.  Toxoplasmosis of Animals and Man , 1989 .

[14]  H. Itazaki,et al.  Isolation and structural elucidation of new cyclotetrapeptides, trapoxins A and B, having detransformation activities as antitumor agents. , 1990, The Journal of antibiotics.

[15]  M. Yoshida,et al.  Trapoxin, an antitumor cyclic tetrapeptide, is an irreversible inhibitor of mammalian histone deacetylase. , 1993, The Journal of biological chemistry.

[16]  V. Georgiev,et al.  Opportunistic infections: Treatment and developmental therapeutics of cryptosporidiosis and isosporiasis , 1993 .

[17]  D. Roos,et al.  Molecular tools for genetic dissection of the protozoan parasite Toxoplasma gondii. , 1994, Methods in cell biology.

[18]  J. P. Davis,et al.  A massive outbreak in Milwaukee of cryptosporidium infection transmitted through the public water supply. , 1994, The New England journal of medicine.

[19]  R. Guerrant,et al.  Household Epidemiology of Cryptosporidium parvum Infection in an Urban Community in Northeast Brazil , 1994, Annals of Internal Medicine.

[20]  J. Walton,et al.  Inhibition of maize histone deacetylases by HC toxin, the host-selective toxin of Cochliobolus carbonum. , 1995, The Plant cell.

[21]  S. J. Upton,et al.  Development of a microtitre ELISA to quantify development of Cryptosporidium parvum in vitro. , 1995, FEMS microbiology letters.

[22]  S. Schreiber,et al.  A Mammalian Histone Deacetylase Related to the Yeast Transcriptional Regulator Rpd3p , 1996, Science.

[23]  C. Allis,et al.  Tetrahymena Histone Acetyltransferase A: A Homolog to Yeast Gcn5p Linking Histone Acetylation to Gene Activation , 1996, Cell.