Protein farnesyltransferase inhibitors exhibit potent antimalarial activity

Laxman Nallan, Kevin D. Bauer, Pravin Bendale, Kasey Rivas, Kohei Yokoyama, Carolyn P. Hornéy, Prakash Rao Pendyala, David Floyd, Louis J. Lombardo, David K. Williams, Andrew Hamilton, Said Sebti, William T. Windsor, Patricia C. Weber, Frederick S. Buckner, Debopam Chakrabarti, Michael H. Gelb, Wesley C. Van Voorhis

Research output: Contribution to journalArticle

Abstract

New therapeutics to combat malaria are desperately needed. Here we show that the enzyme protein farnesyltransferase (PFT) from the malaria parasite Plasmodium falciparurn (P. falciparum) is an ideal drug target. PFT inhibitors (PFTIs) are well tolerated in man, but are highly cytotoxic to P. falciparum. Because of their anticancer properties, PFTIs comprise a highly developed class of compounds. PFTIs are ideal for the rapid development of antimalarials, allowing "piggy-backing" on previously garnered information. Low nanomolar concentrations of tetrahydroquinoline (THQ)-based PFTIs inhibit P. falciparum PFT and are cytotoxic to cultured parasites. Biochemical studies suggest inhibition of parasite PFT as the mode of THQ cytotoxicity. Studies with malaria-infected mice show that THQ PFTIs dramatically reduce parasitemia and lead to parasite eradication in the majority of animals. These studies validate P. falciparum PFT as a target for the development of antimalarials and describe a potent new class of THO PFTIs with antimalaria activity.

Original languageEnglish (US)
Pages (from-to)3704-3713
Number of pages10
JournalJournal of Medicinal Chemistry
Volume48
Issue number11
DOIs
StatePublished - Jun 2 2005

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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  • Cite this

    Nallan, L., Bauer, K. D., Bendale, P., Rivas, K., Yokoyama, K., Hornéy, C. P., Pendyala, P. R., Floyd, D., Lombardo, L. J., Williams, D. K., Hamilton, A., Sebti, S., Windsor, W. T., Weber, P. C., Buckner, F. S., Chakrabarti, D., Gelb, M. H., & Van Voorhis, W. C. (2005). Protein farnesyltransferase inhibitors exhibit potent antimalarial activity. Journal of Medicinal Chemistry, 48(11), 3704-3713. https://doi.org/10.1021/jm0491039