DND Working Group Expert Paper
It is ironic that more is known about the molecular biology, biochemistry, cell biology, immunology, and genetics of members of the kinetoplastidae family of parasitic protozoa than any other parasite, yet the drugs currently used to treat these diseases were discovered empirically, decades ago. While it is difficult to get an accurate figure for worldwide research expenditure on this group of organisms, one measure is the proportion of abstracts presented at meetings such as the Molecular Parasitology Meeting in Woods Hole where more than 70% of the 450 abstracts focus on Leishmania or Trypanosomes. This is an active and vibrant area of basic research, and has received continued support from foundations (e.g., the Wellcome Trust, the Burroughs-Wellcome Fund, Fundação Oswaldo Cruz) and national and international research funding agencies (e.g., National Institutes of Health, Medical Research Council, the Netherlands, Centre National de la Recherche Scientifique in France, and the World Health Organization Special Programme for Research and Training in Tropical Diseases (TDR). Yet, despite this relatively large amount of effort (at least compared to that for other parasitic diseases), the results have not translated into new drug development. Why?
The reasons for the lack of progress in drug development are certainly complex, but are related to the lack of appropriately sized markets for any drugs for these diseases. In many ways these are among the most neglected diseases from the standpoint of drug development. This paper seeks to define potentially viable drug target opportunities for the future. There is an enormous knowledge base for these organisms and new information is being generated at a rapid rate through genome sequencing and the development of novel and sophisticated approaches to functional genomics. With a few exceptions, this knowledge is not being translated into practical next-step applications in the drug development process.
One of the goals of this article is to point to some exciting examples that are now on the horizon and to describe some of the many unique features of these organisms that may lead to identification of new pathways to target in future drug development. The biology of Leishmania sp., Trypanosome brucei, and Trypanosome cruzi are relatively well-described. Each organism has unique aspects to its life cycle; for example, the African trypanosomes do not have an intracellular stage, whereas, in both Leishmania and Trypanosoma cruzi infections, the parasite is primarily intracellular in the mammalian host. Thus, targeting drugs to these organisms will present different challenges. Despite somewhat dramatic differences in biology, the organisms share many of the same metabolic pathways and, although full data are not yet available, they appear to have a very similar arrangement of genes on their chromosomes. This implies a strong relatedness in this group of organisms, and there is certainly the possibility that pathways targeted in one organism may also be viable targets in the others.
The fundamental objective in developing a new drug for any infectious disease is that the drug will stop the infection but will not have any major side effects on the human host. There are several strategies to achieve this objective, but one that has proven valuable in the identification of new drugs for bacteria and viruses is the discovery of unique processes in the microorganism, for example, the reverse transcriptase enzyme in HIV. Such unique enzymes— the proteins that mediate the process, serve as “targets” for drug development. Drugs that inhibit the function of the enzyme can prevent the organism from replicating and thereby prevent the infection from progressing. Knowledge of an organism’s genome and biology can greatly facilitate the discovery of such unique processes and lead to the identification of new “targets” for drug development. One of the great promises of fundamental research in infectious organisms is that such knowledge will lead to the development of new drugs; for the kinetoplastidae parasites, several such unique processes have been identified. The challenge is to turn that knowledge into useful applications.