Design and synthesis of peptidomimetic protein farnesyltransferase inhibitors as anti-Trypanosoma brucei agents.
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.
Ohkanda
Junko
J
Department of Chemistry, Yale University, PO Box 208107, New Haven, Connecticut 06520, USA.
Buckner
Frederick S
FS
Lockman
Jeffrey W
JW
Yokoyama
Kohei
K
Carrico
Dora
D
Eastman
Richard
R
de Luca-Fradley
Kate
K
Davies
Wendy
W
Croft
Simon L
SL
Van Voorhis
Wesley C
WC
Gelb
Michael H
MH
Sebti
Saïd M
SM
Hamilton
Andrew D
AD
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
D007093:Imidazoles; D010455:Peptides; D014344:Trypanocidal Agents; D008715:Methionine; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase