Antimalarial drug discovery: targeting protein kinases

Abstract

Protein kinases (PKs) are prime targets for drug discovery in a variety of diseases, including cancer and neurodegenerative pathologies. The characterisation of the kinome of the human malaria parasite Plasmodium falciparum has revealed profound divergences, at several levels, between PKs of the parasite and those of its host. Here, the authors review the major issues and recent advances regarding the development of Plasmodium-selective PK inhibitors, with emphasis on target identification and validation, and on structure-based design. The authors also discuss the possibility of interfering with: i) Plasmodium PKs regulating transmission to the mosquito vector; and ii) host PKs that may be required for parasite survival.

Keywords::

• malaria
• Plasmodium
• protein kinase
• selectivity
• structure-based design
• transmission-blocking

Acknowledgements

This work was supported the following grants from the EEC (FP6-2002-Life Sciences & Health): PRO-KINASE (LM), SIGMAL (CD and LM) and ANTIMAL (CD and LM). The authors gratefully acknowledge Jane Endicott and Martin Noble (Laboratory of Molecular Biophysics, University of Oxford) for the permission to cite unpublished work on the PfPK7 structure performed in their laboratory and for useful comments on the manuscript, and Paul Liberator (Merck Laboratories) for reviewing the section on Compound 1. The authors thank all members of their own groups for their commitment and for the agreement to cite their unpublished work in this review. The authors apologise to all of their colleagues whose work could not be mentioned in this short review because of space constraints.