Protein Farnesyltransferase Inhibitors Exhibit Potent Antimalarial Activity

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. falcipar...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2005-06, Vol.48 (11), p.3704-3713
Main Authors: Nallan, Laxman, Bauer, Kevin D, Bendale, Pravin, Rivas, Kasey, Yokoyama, Kohei, Hornéy, Carolyn P, Pendyala, Prakash Rao, Floyd, David, Lombardo, Louis J, Williams, David K, Hamilton, Andrew, Sebti, Said, Windsor, William T, Weber, Patricia C, Buckner, Frederick S, Chakrabarti, Debopam, Gelb, Michael H, Van Voorhis, Wesley C
Format: Article
Language:English
Subjects:
Alkyl and Aryl Transferases - antagonists & inhibitors
Animals
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antimalarials - chemical synthesis
Antimalarials - chemistry
Antimalarials - pharmacology
Antiparasitic agents
Biological and medical sciences
Cells, Cultured
Electrophoresis, Polyacrylamide Gel
Erythrocytes - drug effects
Erythrocytes - parasitology
Farnesyltranstransferase
Female
Humans
Malaria - drug therapy
Medical sciences
Mice
Mice, Inbred BALB C
Microscopy, Fluorescence
Pharmacology. Drug treatments
Plasmodium berghei
Plasmodium falciparum
Plasmodium falciparum - drug effects
Plasmodium falciparum - enzymology
Plasmodium falciparum - growth & development
Protein Prenylation
Quinolones - chemical synthesis
Quinolones - chemistry
Quinolones - pharmacology
Rats
Structure-Activity Relationship
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0491039