Title

Protein farnesyltransferase inhibitors exhibit potent antimalarial activity

Authors

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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