A new drug discovery pipeline for animal African trypanosomiasis

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A disproportionate burden of the world's infectious diseases (both human and veterinary) fall upon the African continent. Among the most devastating of the infectious agents of animals are the trypanosomes that cause Animal African Trypanosomosis (AAT). Transmitted primarily by tsetse and other biting flies, the disease is present in 40 African countries and affects nearly all domestic animals. The overall economic losses attributable to AAT are estimated at $4.75 billion per annum. These are losses borne principally by those who can least afford them: small-scale subsistence farmers and rural communities in AAT-affected areas of large parts of sub-Saharan Africa who rely on livestock for their livelihoods. Current AAT control tools rely extensively on trypanocidal drugs for the treatment of infected animals and for prophylaxis of infection. The drugs are widely available but were developed over 50 years ago and have significant limitations in terms of safety and increasingly lack efficacy against emergent drug-resistant trypanosomes.Over ten million km2 of Africa are infested by tsetse flies and thus affected by AAT; this represents a substantial portion of Africa's fertile and watered land. Within this area, millions of small-scale livestock keepers rely on an estimated 55 million cattle and 70 million sheep and goats for their livelihoods and food security. These regions are under sustained and increasing pressure to produce more food for growing populations, increasing per capita consumption of meat and dairy products, climate change and desertification all combine to require increased agricultural output within the potentially productive areas of sub-Saharan Africa. Losses arising from AAT are both direct (e.g. estimated annual death of 3 million cattle) and indirect as a result of productivity losses (e.g. benefits of up to $7,000 per km2 from removing AAT). The net effect is a significant constraint on growth and development of the dairy and beef sectors, as well as sheep and goat rearing in the regions affected. Trypanocidal drugs are the mainstay in the control of AAT because of the absence of realistic prospects for vaccines. Vector control has had limited success and showed poor sustainability, the more so in areas where non-tsetse fly transmission is important (e.g. parts of Africa, but particularly in the Far East and South America too).The Global Alliance for Livestock Veterinary Medicine (GALVmed) was founded to help channel global efforts into amelioration of the burden placed upon the world's food security brought about by various infectious diseases. With substantial funding from the UK Department for International Development and the Bill and Melinda Gates Foundation, GALVmed has become the primary agency involved in efforts to bring new drugs forward to treat AAT.In this proposal, experts at the Universities of Glasgow and Strathclyde, and the Roslin Institute of the University of Edinburgh, are coming together to develop a new class of compounds that has been shown to have profound efficacy against the causative agents of AAT, both in vitro and in rodent models of the disease. Chemical structures of those compounds optimised for trypanocidal activity in cattle will be developed with the intention of taking them into clinical development. We will additionally develop new culture systems for the relevant parasite species - a crucial step for rapid and routine screening of our candidate drugs but also large sets of unrelated compounds (chemical libraries), with minimal need for tests in animals. We will also use state of the art biological and computational methods to learn about the internal functioning of the causative parasites, in order to understand how this new class of compound works. This part of the project will also provide key information to allow other classes of compounds to be brought forward, giving an important input to a long-term pipeline of new drugs to treat AAT.