When basic scientists undertake to study the molecular basis of Leishmania transmission from sandfly to man, or the sophisticated ways in which trypanosomes have evolved to evade immune surveillance, or the 3D structure of a unique parasite enzyme, they do so out of sheer scientific curiosity. Using increasingly sophisticated research tools (e.g., bio-engineering, bio-informatics, structural biology) they relentlessly pursue new knowledge and insights from their academic ivory towers. They believe it is up to others to translate this knowledge into applications.

The goals and rewards of basic scientists are publications in high-ranking scientific journals, and concomitant career and research funding prospects. Indeed, the public scientific community is governed by the publish-or-perish principle, and research progress is more readily published when it is the result of innovative approaches and technologies, tackles a new research question, or provides new or unexpected insights etc.

In drug discovery, this means that most of the innovation is in the identification of possible new drug targets (preferably with a beautiful 3D structure to present at conferences), or the discovery that selective inhibitors of such a target can be generated. But that is still a far cry from finding a new drug candidate. Indeed, once a selective inhibitor of a parasite is identified (a “hit”), it takes 2-4 years of continuous research by a multidisciplinary team to transform it into a drug lead, and then into a drug candidate that can be tested for use against the disease in humans.

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In essence, this hit-to-lead-to-candidate optimisation activity involves the synthesis of many compounds that closely resemble the identified inhibitor, and an iterative assessment of these compounds in a series of predefined, routine tests to identify the best ones in terms of drug candidate. And there lies the problem.

1. Lack of excitement and publications
For basic researchers, the science needed to obtain a good drug candidate is neither innovative nor exciting. After the more creative design and synthesis of new compounds, there is little scientific interest in performing standard assays for biological activity against the parasite and the wide range of routine pharmacological, toxicological and physicochemical tests to evaluate the “druggability” (drug-like nature) of these compounds. At best, this repetitive, labour-intensive process involving hundreds to thousands of similar compounds might result in just one serious drug candidate with some back-up compounds, and maybe one publication. Poor reward for a high-flying academic in a public research setting.2. Multidisciplinary process
An additional hindrance is the multidisciplinary nature of this endeavour. Today, few public research groups exist that have at their disposal all the expertise, methods, and technologies for these different tests. As a result, while drug discovery research efforts generally start within the biology/parasitology groups, optimisation will tend to focus on biological activity while neglecting the pharmaceutical druggability part. Needless to say, this process is more productive in terms of publications than drug candidates!

In recent years, however, things have started to change. Several public research groups around the world have started to expand their expertise and focus beyond early drug discovery to also encompass the next steps of lead optimisation following drug development criteria, particularly in disease areas where the pharmaceutical industry has been largely absent, such as tropical and parasitic diseases or tuberculosis.In fact, one initiative has chosen to focus mainly on human African trypanosomiasis, Chagas disease and leishmaniasis: the Drug Discovery for Tropical Diseases initiative (DDTD) at the University of Dundee (see interview with Alan Fairlamb, page 3). This initiative and other recent efforts to revive neglected disease drug development efforts in public research (University of California, San Francisco; Broad Institute at Harvard; National Institutes of Health; Walter and Eliza Hall Institute etc.) as well as industry (GSK’s facility at Tres Cantos Spain, the Novartis Institute for Tropical Diseases Singapore, and some biotech companies) will be crucial to feeding the R&D pipelines of DNDi and other initiatives.