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 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.

• Authors: 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 48 Issue 11 Pg. 3704-13 (Jun 02 2005) ISSN: 0022-2623 [Print] United States
• PMID: 15916422 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antimalarials
• Quinolones
• Alkyl and Aryl Transferases
• Farnesyltranstransferase

Topics

• Alkyl and Aryl Transferases (antagonists & inhibitors)
• Animals
• Antimalarials (chemical synthesis, chemistry, pharmacology)
• Cells, Cultured
• Electrophoresis, Polyacrylamide Gel
• Erythrocytes (drug effects, parasitology)
• Farnesyltranstransferase
• Female
• Humans
• Malaria (drug therapy)
• Mice
• Mice, Inbred BALB C
• Microscopy, Fluorescence
• Plasmodium berghei
• Plasmodium falciparum (drug effects, enzymology, growth & development)
• Protein Prenylation
• Quinolones (chemical synthesis, chemistry, pharmacology)
• Rats
• Structure-Activity Relationship