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. 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.
Nallan
Laxman
L
Department of Chemistry, University of Washington, Seattle, Washington 98195, USA.
Bauer
Kevin D
KD
Bendale
Pravin
P
Rivas
Kasey
K
Yokoyama
Kohei
K
Hornéy
Carolyn P
CP
Pendyala
Prakash Rao
PR
Floyd
David
D
Lombardo
Louis J
LJ
Williams
David K
DK
Hamilton
Andrew
A
Sebti
Said
S
Windsor
William T
WT
Weber
Patricia C
PC
Buckner
Frederick S
FS
Chakrabarti
Debopam
D
Gelb
Michael H
MH
Van Voorhis
Wesley C
WC
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
D000962:Antimalarials; D015363:Quinolones; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase