Title
Protein Prenyltransferases as Potential Targets for Development of Novel Antimalarials
Abstract
Prenylated proteins have been shown to function in important cellular regulatory processes including signal transduction. Protein farnesyltransferase (PFT) and geranylgeranyl transferase-I (PGGT-I) have been recent targets for development of cancer drugs. We have identified PFT and PGGT-I in the malaria parasite, Plasmodium falciparum, and initiated a study to determine whether these enzymes can be developed as targets for antimalarial chemotherapy. PFT has been partially purified from the cytosolic fraction through ammonium sulfate precipitation and Mono-Q chromatography. PFT and PGGT-I activities are present at all stages of P. falciparum intraerythrocytic development with maximum activity in the ring stage. PGGT-I activity is two times PFT activity in the ring stage. Peptidomimetics and prenyl analogues of PFT substrates were tested as inhibitors of Mono-Q purified enzyme and of malaria parasite growth. Both in vitro and in vivo testing of these inhibitors showed that the peptidomimetics were significantly more potent than lipid substrate analogues. Exposure of the parasite to the peptidomimetic L745,631 also showed significant morphological effects during ring to schizont transition but not during progression of the parasite from schizont to trophozoite. These studies suggest the feasibility of designing or identifying differential inhibitors of P. falciparum and mammalian prenyl t ran sferases as an approach to malaria therapy.
Publication Date
12-1-1998
Publication Title
FASEB Journal
Volume
12
Issue
8
Document Type
Article
Personal Identifier
scopus
Copyright Status
Unknown
Socpus ID
33749098978 (Scopus)
Source API URL
https://api.elsevier.com/content/abstract/scopus_id/33749098978
STARS Citation
Allen, C. M.; Chakrabarti, D.; and Azam, T., "Protein Prenyltransferases as Potential Targets for Development of Novel Antimalarials" (1998). Scopus Export 1990s. 3623.
https://stars.library.ucf.edu/scopus1990/3623