ABSTRACT
Apicidin, a natural product recently isolated at Merck, inhibits both mammalian and protozoan histone deacetylases (HDACs). The conversion of apicidin, a nanomolar inhibitor of HDACs, into a series of side-chain analogues that display picomolar enzyme affinity is described within this structure-activity study.
Subject(s)
Antiprotozoal Agents/chemical synthesis , Histone Deacetylase Inhibitors , Peptides, Cyclic/pharmacology , Animals , Antiprotozoal Agents/pharmacology , Biological Factors/pharmacology , Cattle , Cell Line , Combinatorial Chemistry Techniques , Eimeria tenella/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Fusarium/chemistry , HeLa Cells , Humans , Microbial Sensitivity Tests , Peptides, Cyclic/chemical synthesis , Plasmodium falciparum/drug effects , Structure-Activity RelationshipABSTRACT
Recently isolated at Merck, apicidin inhibits both mammalian and protozoan histone deacetylases (HDACs). The conversion of apicidin, a nonselective nanomolar inhibitor of HDACs, into a series of picomolar indole-modified and parasite-selective tryptophan-replacement analogues is described within this structure-activity study.
Subject(s)
Antiprotozoal Agents/chemical synthesis , Histone Deacetylase Inhibitors , Peptides, Cyclic/pharmacology , Animals , Antiprotozoal Agents/pharmacology , Biological Factors/pharmacology , Cattle , Cell Division/drug effects , Cell Line , Combinatorial Chemistry Techniques , Eimeria tenella/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Fusarium/chemistry , HeLa Cells , Humans , Indoles/chemistry , Microbial Sensitivity Tests , Peptides, Cyclic/chemical synthesis , Plasmodium falciparum/drug effects , Structure-Activity Relationship , Tryptophan/chemistryABSTRACT
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.
