Proteinases as Drug Targets
Chapter 7: Plasmodium falciparum Neutral Aminopeptidases: Development of Novel Anti-Malarials by Understanding Enzyme Structure
Published:22 Nov 2011
Special Collection: 2011 ebook collection , 2011 ebook collection , 2011-2015 organic chemistry subject collectionSeries: Drug Discovery
D. Gardiner, J. Dalton, and S. McGowan, in Proteinases as Drug Targets, ed. B. Dunn, The Royal Society of Chemistry, 2011, ch. 7, pp. 169-185.
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Malaria is the world's most prevalent human parasitic disease. Because of the rapid spread of drug resistance in the parasite, there is an urgent need to identify new diverse drug targets. Within the complex intra-erythrocytic life-cycle of the parasite, the activity of two neutral metalloaminopeptidases is essential to the parasite's growth and development. Inhibition of the combined activity of the m1 alanyl aminopeptidase and the m17 leucyl aminopeptidase prevents the growth of Plasmodium falciparum parasites in culture, and protects mice from infection with the rodent malaria species P. c. chabaudi, providing strong support for considering them as targets for which a new class of anti-malarial drugs can be developed. The high-resolution X-ray crystal structures of both enzymes have been elucidated and provide valuable structural and mechanistic detail to facilitate the development of compounds in future rational drug-design programs.