Design and Synthesis of Peptidomimetic Protein Farnesyltransferase Inhibitors as Anti-Trypanosoma brucei Agents

Junko Ohkanda, Frederick S. Buckner, Jeffrey W. Lockman, Kohei Yokoyama, Dora Carrico, Richard Eastman, Kate De Luca-Fradley, Wendy Davies, Simon L. Croft, Wesley C. Van Voorhis, Michael H. Gelb, Saïd M. Sebti, Andrew D. Hamilton

Research output: Contribution to journalArticle

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 ED50 values of 0.025 and 0.0026 μM, respectively. Furthermore, introducing a second imidazole group into 23 led to 31, which showed the highest inhibition activity against the parasite with an ED50 of 0.0015 μM. 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.

Original languageEnglish (US)
Pages (from-to)432-445
Number of pages14
JournalJournal of Medicinal Chemistry
Volume47
Issue number2
DOIs
StatePublished - Jan 15 2004

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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  • Cite this

    Ohkanda, J., Buckner, F. S., Lockman, J. W., Yokoyama, K., Carrico, D., Eastman, R., De Luca-Fradley, K., Davies, W., Croft, S. L., Van Voorhis, W. C., Gelb, M. H., Sebti, S. M., & Hamilton, A. D. (2004). Design and Synthesis of Peptidomimetic Protein Farnesyltransferase Inhibitors as Anti-Trypanosoma brucei Agents. Journal of Medicinal Chemistry, 47(2), 432-445. https://doi.org/10.1021/jm030236o