The effects of protein farnesyltransferase inhibitors on trypanosomatids: inhibition of protein farnesylation and cell growth.
Attachment of the prenyl groups farnesyl and geranylgeranyl to specific eukaryotic cell proteins by protein prenyltransferases is required for the functioning of a number of cellular processes including signal transduction. In this study it was found that previously reported inhibitors of mammalian protein farnesyltransferase (PFT) [those that mimic the substrate farnesyl pyrophosphate and those that mimic the protein acceptor of the farnesyl group (CaaX mimetic)] inhibit in vitro farnesylation catalyzed by partially purified Trypanosoma brucei (T. brucei) PFT. The most potent PFT inhibitors at concentrations of 3-10 microM inhibit the growth of insect (procyclic) and bloodstream forms of T. brucei. One of the PFT inhibitors was found to block the incorporation of radiolabeled mevalonic acid (the precursor of prenyl groups) into specific T. brucei proteins. This study also shows that protein prenylation occurs in the protozoan parasites Trypanosoma cruzi (T. cruzi) and Leishmania mexicana (L. mexicana). The growth of T. cruzi intracellular form (amastigote) is also sensitive to PFT inhibitors, whereas the insect form (epimastigote) is considerably more resistant to inhibition of protein farnesylation. On the other hand, growth of 3T3 fibroblast cells (host cells for amastigote growth) was not affected by up to 100 microM PFT inhibitors. The growth of L. mexicana insect form (promastigote) is modestly inhibited by protein farnesyltransferase inhibitors. These results suggest the potential for the development of PFT inhibitors for treating trypanosomiasis and leishmaniasis.
Department of Chemistry, University of Washington, Seattle 98195-1700, USA.
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K
Yokoyama
P
P
Trobridge
F S
FS
Buckner
J
J
Scholten
K D
KD
Stuart
W C
WC
Van Voorhis
M H
MH
Gelb
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D004591:Electrophoresis, Polyacrylamide Gel; D005347:Fibroblasts / Q000187:drug effects; D005470:Fluorometry; D007894:Leishmania mexicana / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D008858:Microscopy, Phase-Contrast; D017368:Protein Prenylation / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development
D019821:Simvastatin; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase