On a treasure hunt
There is no recipe for drug discovery – it is like a treasure hunt. But where does it all begin?
DNDi’s portfolio has projects on target enzymes, for example, trypanothione reductase and cysteine protease, that use rational drug design - 200,000 compounds have been tested on trypanothione reductase to find those that will inhibit this target enzyme. The best example of a product that has come from this type of discovery is the anti-influenza drug currently making waves – Tamiflu®.

A second more traditional method of drug discovery is empirical screening. In this process a library of tens of thousands of compounds of diverse structure is screened against a known target or a whole organism. The compounds that inhibit the target enzyme or kill the pathogen at the lowest concentrations are selected. These compounds are subsequently tested against the homologous mammalian enzyme or a mammalian cell line to show whether they have “selectivity”, that is to test if they are able to kill the pathogen at a 100-fold lower concentration than the mammalian cell.

DNDi supports some screening projects, for example at the Kitasato Institute, Tokyo, where the anti-filarial drug ivermectin was discovered using this approach.

The third way that drugs are discovered is by making connections. The activity of eflornithine against trypanosomes followed basic studies on polyamine biosynthesis in these parasites. Eflornithine had already been developed as an anti-cancer drug that inhibited the essential enzyme, ornithine decarboxylase, in this process; Cy Bacchi (Pace University, New York) made the connection and the drug was soon being used to treat sleeping sickness. Miltefosine for leishmaniasis was discovered in a similar way.

This issue of the DNDi Newsletter is devoted to drug discovery, and several critical parts of the pathway are amply described within.  An in-depth knowledge of the target, the assay system, and the chemistry is essential in making the connections and assessing whether you have a “hit”.

Having the eternal optimism of a treasure hunter also helps.

Simon Croft, R&D Director, DNDi
Published by Drugs for Neglected Diseases Initiative - 1 Place St Gervais 1201 Geneva Switzerland
Editor: Jaya Banerji - Tel: +41 22 906 9230 - Fax: +41 22 906 9231 - www.dndi.org