Metabolic analysis in drug design

Biotechnology is often presented as if progress in the past two decades represented a major success, but the reality is quite different. For example. ten major classes of antibiotics were discovered between 1935 and 1963, but after 1963 there has been just one. the oxazolidones. To illustrate the possibilities of doing better by taking account of the real behaviour of metabolic systems. we can examine how one might modify the activity of an enzyme in the cell (for example by genetic manipulation, or by the action of an inhibitor, etc.) to satisfy a technological aim. For example, if the objective is to eliminate a pest, one might suppose that the effect of an inhibitor could be to depress an essential flux to a level insufficient for life, or to raise the concentration of an intermediate to a toxic level. The former may seem the more obvious, but the latter is easier to achieve in practice, and there are some excellent examples of industrial products that work in that way, such as the herbicide 'Roundup' and antimalarials of the quinine class. A study of glycolysis in the parasite Trypanosoma brucei (which causes African sleeping sickness) indicates that for this approach to work the selected target enzyme must have a substrate with a concentration that is not limited by stoichiometric constraints. That is not necessarily easy to find in a complicated system, and typically needs the metabolic network to be analysed in the computer. (C) 2003 Academie des sciences. Published by Editions scientifiques et medicales Elsevier SAS. All rights reserved.