African sleeping sickness affects the developing countries of sub-Saharan Africa threatening >70 million people. More formally known as Human African trypanosomiasis it is transmitted to humans by the bite of the tsetse fly carrying the protozoan parasite Trypanosoma brucei. African sleeping sickness is one of the greatest causes of social and economic hardship, as well as mortality. Over 95% of reported cases are found in West and Central Africa caused by a T. brucei gambinese infection, with the likely numbers of infected people being significantly higher than those reported. Untreated, sleeping sickness is invariably fatal. Early stage treatment is advantageous, and yet it is often only when the parasite crosses the blood brain barrier that the characteristic symptoms of the disease become apparent. Current treatments for this neglected disease are limited to a range of largely ineffective, highly toxic, hard to administer drugs, and increasing drug resistance is becoming a critical problem.
By taking inspiration from nature, our vision is to establish an integrated multidisciplinary research programme into the development of novel and highly selective therapeutic agents for the treatment of Human African trypanosomiasis. The annonaceous acetogenin family of natural products provides a previously unexplored molecular blueprint for the development of natural product-inspired trypanocidal drugs, despite the widespread use of annonaceae plant extracts in traditional medicinal practices across sub-Saharan Africa. The challenge is to combine expertise in the fields of natural product synthesis and cutting-edge molecular parasitology to bring about a step change in drug discovery for this neglected disease.
Following our work on the synthesis of chamuvarinin, an acetogenin isolated from the roots of the Uvaria Chamae in Senegal, we have demonstrated the potential of this approach via a series of highly simplified analogue structures which killed T. brucei at low micromolar levels and more significantly are inactive towards mammalian cells.
Building upon these preliminary findings, this research programme is centred on the design and optimisation of new chemical entities with tailored ‘natural product-like’ characteristics and biological properties. To achieve these goals a synergistic relationship is needed uniting synthetic organic chemistry and molecular parasitology, in order to further our understanding of how our novel chemotherapeutic agents promote cell death in the parasite responsible for African sleeping sickness. The discovery of novel pathways for inhibition in concert with rational drug design are central to our approach, and their realisation will ultimately facilitate the translation from laboratory to clinic in the form of a new generation of effective treatments for this disease.
Dr Gordon Florence
Gordon was awarded a Research Leadership Award in 2012.
Preliminary analogues of the natural product chamuvarinin have displayed potent and selective activity towards T. brucei in phenotypic assays. Structural optimisation of hits coupled with the identification and biological validation of the specific parasite protein target will enable the potential development of a new generation of HAT inhibitors.