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.
Darkin-Rattray
S J
SJ
Department of Parasite Biochemistry, Merck Research Laboratories, Rahway, NJ 07065, USA.
Gurnett
A M
AM
Myers
R W
RW
Dulski
P M
PM
Crumley
T M
TM
Allocco
J J
JJ
Cannova
C
C
Meinke
P T
PT
Colletti
S L
SL
Bednarek
M A
MA
Singh
S B
SB
Goetz
M A
MA
Dombrowski
A W
AW
Polishook
J D
JD
Schmatz
D M
DM
D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D016786:Eimeria tenella / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056890:Eukaryota / Q000187:drug effects*; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007700:Kinetics; D008288:Malaria / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D018688:Neospora / Q000187:drug effects; D010456:Peptides, Cyclic / Q000494:pharmacology* / Q000627:therapeutic use; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects; D011485:Protein Binding; D011528:Protozoan Infections / Q000188:drug therapy; D013329:Structure-Activity Relationship; D014122:Toxoplasma / Q000187:drug effects
D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; C102351:apicidin; C037654:HC toxin