Protein Farnesyltransferase Inhibitors Exhibit Potent Antimalarial Activity
- 5 May 2005
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 48 (11) , 3704-3713
- https://doi.org/10.1021/jm0491039
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.Keywords
This publication has 12 references indexed in Scilit:
- Design, synthesis, and structure–activity relationships of tetrahydroquinoline-based farnesyltransferase inhibitorsBioorganic & Medicinal Chemistry Letters, 2005
- In vitro and in vivo antimalarial activity of peptidomimetic protein farnesyltransferase inhibitors with improved membrane permeabilityBioorganic & Medicinal Chemistry, 2004
- Identification of an antimalarial synthetic trioxolane drug development candidateNature, 2004
- Farnesyltransferase‐Inhibitoren hemmen das Wachstum von Malaria‐Erregern in vitro und in vivoAngewandte Chemie, 2003
- Design and Synthesis of Peptidomimetic Protein Farnesyltransferase Inhibitors as Anti-Trypanosoma brucei AgentsJournal of Medicinal Chemistry, 2003
- Sch-66336 (sarasar) and other benzocycloheptapyridyl farnesyl protein transferase inhibitors: discovery, biology and clinical observations.Current Topics in Medicinal Chemistry, 2003
- Differential Prenyl Pyrophosphate Binding to Mammalian Protein Geranylgeranyltransferase-I and Protein Farnesyltransferase and Its Consequence on the Specificity of Protein PrenylationPublished by Elsevier ,1997
- Protein prenyltransferasesBiochemical Society Transactions, 1992
- Formation of olefins via pyrolysis of sulfonate estersThe Journal of Organic Chemistry, 1989
- Human Malaria Parasites in Continuous CultureScience, 1976