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 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.affiliation: Department of Chemistry, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Laxman
authors.initials: L
authors.lastname: Nallan
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Bauer
authors.forename: Pravin
authors.initials: P
authors.lastname: Bendale
authors.forename: Kasey
authors.initials: K
authors.lastname: Rivas
authors.forename: Kohei
authors.initials: K
authors.lastname: Yokoyama
authors.forename: Carolyn P
authors.initials: CP
authors.lastname: Hornéy
authors.forename: Prakash Rao
authors.initials: PR
authors.lastname: Pendyala
authors.forename: David
authors.initials: D
authors.lastname: Floyd
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Lombardo
authors.forename: David K
authors.initials: DK
authors.lastname: Williams
authors.forename: Andrew
authors.initials: A
authors.lastname: Hamilton
authors.forename: Said
authors.initials: S
authors.lastname: Sebti
authors.forename: William T
authors.initials: WT
authors.lastname: Windsor
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Weber
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Buckner
authors.forename: Debopam
authors.initials: D
authors.lastname: Chakrabarti
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gelb
authors.forename: Wesley C
authors.initials: WC
authors.lastname: Van Voorhis
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D051231:Farnesyltranstransferase; D005260:Female; D006801:Humans; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D017368:Protein Prenylation; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D015363:Quinolones; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase