On the mathematical modelling of metabolic pathways and its use in the identification of the most suitable drug target.

Parasitic diseases are a present and worsening threat to human health and welfare around the globe. Yet current products and tools for the treatment of most parasitic diseases are predominantly limited in scope, effect and availability. Drug resistance is spreading rapidly, the development of new drugs is not keeping pace with need, and many potential vaccines have not been meeting expectations. This report details the proceedings of a meeting on "Drugs against parasitic diseases", held in Montpellier, France (24-26 1999). The goal of the meeting was the production of a basic framework to better coordinate and guide research and development of antiparasitic drugs. The meeting addressed various questions concerning drug discovery and development, with particular attention being paid to novel strategies and new technologies. There was a special focus on the promise and pitfalls of parasite genomics. The papers presented at the meeting (and published in this report) cover a selection of top priorities that would benefit from immediate R&D activities. They also attempt to provide guidance that could be used to accelerate the general development of antiparasitic drugs

The mitochondrial FAD-dependent glycerol-3-phosphate dehydrogenase of Trypanosomatidae and the glycocomal redox balance of insect stages of Trypanosoma brucei and Leishmania spp.

The genes for the mitochondrial FAD-dependent glycerol-3-phosphate dehydrogenase were identified in Trypanosoma brucei and Leishmania major genomes. We have expressed the L. major gene in Saccharomyces cerevisiae and confirmed the subcellular localization and activity of the produced enzyme. Using cultured T. brucei procyclic and Leishmania mexicana promastigote cells with a permeabilized plasma membrane and containing intact glycosomes, it was shown that dihydroxyacetone phosphate is converted into pyruvate, and stimulates oxygen consumption, indicating that all components of the glycerol 3-phosphate/dihydoxyacetone phosphate shuttle between glycosomes and mitochondrion are present in these insect stages of both organisms. A computer model has been prepared for the energy and carbohydrate metabolism of these cells. It was used in an elementary mode analysis to get insight into the metabolic role of the shuttle in these insect-stage parasites. Our analysis suggests that the shuttle fulfils important roles for these organisms, albeit different from its well-known function in the T. brucei bloodstream form. It allows (1) a high yield of further metabolizable glycolytic products by decreasing the need to produce a secreted end product of glycosomal metabolism, succinate; (2) the consumption of glycerol and glycerol 3-phosphate derived from lipids; and (3) to keep the redox balance of the glycosome finely tuned due to a highly flexible and redundant system

A new approach to nuclear structure functions

We calculate the structure function of an MIT bag model nucleon bound in self-consistent scalar and vector mean fields corresponding to nuclear matter at an appropriate density. This approach enables us to investigate a number of features of the usual binding correction for the EMC effect. When Fermi motion is included the calculation reproduces the main features of the data.A.W. Thomas, A. Michels, A.W. Schreiber, P.A.M. Guicho