Title

Protein Farnesyltransferase Inhibitors Exhibit Potent Antimalarial Activity

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. © 2005 American Chemical Society.

Publication Date

6-2-2005

Publication Title

Journal of Medicinal Chemistry

Volume

48

Issue

11

Number of Pages

3704-3713

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1021/jm0491039

Socpus ID

20144373679 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/20144373679

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