THE EFFECTS OF PROTEIN FARNESYLTRANSFERASE INHIBITORS ON TRYPANOSOMATIDS - INHIBITION OF PROTEIN FARNESYLATION AND CELL-GROWTH

Attachment of the prenyl groups farnesyl and geranylgeranyl to specifi c eukaryotic cell proteins by protein prenyltransferases is required f or the functioning of a number of cellular processes including signal transduction. In this study it was found that previously reported inhi bitors of mammalian protein farnesyltransferase (PFT) [those that mimi c the substrate farnesyl pyrophosphate and those that mimic the protei n acceptor of the farnesyl group (CaaX mimetic)] inhibit in vitro farn esylation catalyzed by partially purified Trypanosoma brucei (T. bruce i) PFT. The most potent PFT inhibitors at concentrations of 3-10 mu M inhibit the growth of insect (procyclic) and bloodstream forms of T. b rucei. One of the PFT inhibitors was found to block the incorporation of radiolabeled mevalonic acid (the precursor of prenyl groups) into s pecific T. brucei proteins. This study also shows that protein prenyla tion occurs in the protozoan parasites Trypanosoma cruzi (T. cruzi) an d Leishmania mexicana (L. mexicana). The growth of T, cruzi intracellu lar form (amastigote) is also sensitive to PFT inhibitors, whereas the insect form (epimastigote) is considerably more resistant to inhibiti on of protein farnesylation. On the other hand, growth of 3T3 fibrobla st cells (host cells for amastigote growth) was not affected by up to 100 mu M PFT inhibitors. The growth of L, mexicana insect form (promas tigote) is modestly inhibited by protein farnesyltransferase inhibitor s. These results suggest the potential for the development of PFT inhi bitors for treating trypanosomiasis and leishmaniasis. (C) 1998 Elsevi er Science B.V. All rights reserved.