Framework programme:

 7

Contract/Grant agreement number:

223024

EC contribution:

2.100.000 €

Duration:

36 months

Funding scheme:

Small-Medium Collaborative Project (SICA)

Starting date:

01/01/2009

 

 

Keywords: malaria, Plasmodium falciparum, drug development, protein synthesis, drug screening, apicoplast, tRNA, aminoacyl-tRNA synthetases, elongation factors

Background

The protein synthesis machinery represents one of the most useful targets for the development of new anti-infectives. Several families of broadly used antibiotics (tetracyclines, macrolides, and novel glycopeptides like vancomycin, among others) exert their function by blocking the protein synthesis machinery. Doxycycline, a tetracycline antibiotic, remains a useful tool for the prevention of paludism among travellers, despite its numerous secondary effects. But very little is known about the specifics of the protein synthesis machinery in Plasmodium.

Lack of information about this central metabolic pathway in Plasmodium clearly blocks the possibility of transferring the knowledge in protein synthesis to the development of new antimalarial drugs directed against the translational machinery of the parasite. Thus, the study of components of the genetic code in Plasmodium has the potential for providing new and important information on the biology of the parasite and, more importantly, open new leads for the development of novel antimalarials.

Aims and expected results

• MEPHITIS has started to generate its first results towards a better understanding of protein synthesis and the discovery of new protein synthesis inhibitors with anti-malarial activity.
• A large battery of known molecular inhibitors previously uncharacterised in Plasmodium cultures has been tested, and two drugs with powerful inhibitory activity have been identified. Currently these molecules are being tested alone and in combination in animal models of Plasmodium infection to determine their real potential as anti-malarial therapeutics.
• An ambitious effort has also been initiated to obtain crystal structures of crucial components of the protein synthesis apparatus. A broad collaboration within Mephitis is providing crystallography groups in India and Europe with the necessary material to carry out this goal.
• Finally, new and uncharacterised aspects of protein synthesis in Plasmodium are being studied, with a particular emphasis in the analysis of protein synthesis in the apicoplast and in relation to the host’s genetic apparatus.

Coordinator:

Prof. Lluis Ribas de Poulana
IRB Barcelona
Barcelona
Spain
E-mail: lluis.ribas@irbbarcelona.org

Partners: