Protein farnesyltransferase inhibitors exhibit potent antimalarial activity

    Authors

    L. Nallan; K. D. Bauer; P. Bendale; K. Rivas; K. Yokoyama; C. P. Horney; P. R. Pendyala; D. Floyd; L. J. Lombardo; D. K. Williams; A. Hamilton; S. Sebti; W. T. Windsor; P. C. Weber; F. S. Buckner; D. Chakrabarti; M. H. Gelb;W. C. Van Voorhis

    Comments

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    Abbreviated Journal Title

    J. Med. Chem.

    Keywords

    PLASMODIUM-FALCIPARUM; IN-VITRO; MALARIA PARASITES; DESIGN; VIVO; PRENYLATION; DISCOVERY; CULTURE; Chemistry, Medicinal

    Abstract

    New therapeutics to combat malaria are desperately needed. Here we show that the enzyme protein farnesyltransferase (PFT) from the malaria parasite Plasmodium falciparum (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 THQ PFTIs with antimalaria activity.

    Journal Title

    Journal of Medicinal Chemistry

    Volume

    48

    Issue/Number

    11

    Publication Date

    1-1-2005

    Document Type

    Article

    Language

    English

    First Page

    3704

    Last Page

    3713

    WOS Identifier

    WOS:000229443700008

    ISSN

    0022-2623

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