title: Design and synthesis of peptidomimetic protein farnesyltransferase inhibitors as anti-Trypanosoma brucei agents.
abstract: On the basis of the structure of the CVIM tetrapeptide substrate of mammalian protein farnesyltransferase, a series of imidazole-containing peptidomimetics was designed and synthesized, and their inhibition activity against Trypanosoma brucei protein farnesyltransferase (TbPFT) was evaluated. Peptidomimetics where the 5-position of the imidazole ring was linked to the hydrophobic scaffold showed over 70% inhibition activity at 50 nM in the enzyme assay, whereas the corresponding C-4 regioisomers were less potent. The ester prodrug 23 was found to be a potent inhibitor against cultured Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense cells with ED(50) values of 0.025 and 0.0026 microM, respectively. Furthermore, introducing a second imidazole group into 23 led to 31, which showed the highest inhibition activity against the parasite with an ED(50) of 0.0015 microM. The potency of the TbPFT inhibitors and the cytotoxicity of the corresponding esters to T. brucei cells were shown to be highly correlated. These studies validate TbPFT as a target for the development of novel therapeutics against African sleeping sickness.
authors.affiliation: Department of Chemistry, Yale University, PO Box 208107, New Haven, Connecticut 06520, USA.
authors.forename: Junko
authors.initials: J
authors.lastname: Ohkanda
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Buckner
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Lockman
authors.forename: Kohei
authors.initials: K
authors.lastname: Yokoyama
authors.forename: Dora
authors.initials: D
authors.lastname: Carrico
authors.forename: Richard
authors.initials: R
authors.lastname: Eastman
authors.forename: Kate
authors.initials: K
authors.lastname: de Luca-Fradley
authors.forename: Wendy
authors.initials: W
authors.lastname: Davies
authors.forename: Simon L
authors.initials: SL
authors.lastname: Croft
authors.forename: Wesley C
authors.initials: WC
authors.lastname: Van Voorhis
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gelb
authors.forename: Saïd M
authors.initials: SM
authors.lastname: Sebti
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hamilton
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D015195:Drug Design; D051231:Farnesyltranstransferase; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008715:Methionine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects* / Q000201:enzymology
chemical_list: D007093:Imidazoles; D010455:Peptides; D014344:Trypanocidal Agents; D008715:Methionine; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase