A new drug discovery pipeline for animal African trypanosomiasis

非洲大陆承受着世界传染病（人类和兽医）的不成比例的负担。其中最具破坏性的动物感染剂是锥虫，导致动物非洲锥虫病（AAT）。这种疾病主要由采采蝇和其他叮咬苍蝇传播，目前存在于40个非洲国家，几乎影响到所有家畜。反坦克武器造成的整体经济损失估计为每年47.5亿美元。这些损失主要由那些最无力承受的人承担：在撒哈拉以南非洲大部分地区的受地雷影响地区，依靠牲畜维持生计的小规模自给农民和农村社区。目前的AAT控制工具广泛依赖于杀锥虫药物来治疗受感染的动物和预防感染。这些药物是广泛可用的，但在50多年前开发的，在安全性方面有很大的局限性，对新出现的抗药性锥虫越来越缺乏疗效。非洲有一千多万平方公里的土地受到采采蝇的侵扰，因此受到AAT的影响;这代表了非洲肥沃和有水的土地的很大一部分。在这一地区，数百万小型牲畜饲养者依靠约5 500万头牛和7 000万只绵羊和山羊维持生计和粮食安全。这些区域承受着为不断增长的人口生产更多粮食的持续和越来越大的压力，肉类和奶制品的人均消费量不断增加，气候变化和荒漠化联合收割机加在一起，都要求增加撒哈拉以南非洲潜在生产地区的农业产量。农业可消化物造成的损失既有直接的（例如，估计每年有300万头牛死亡），也有生产力损失造成的间接损失（例如，消除农业可消化物可带来每平方公里高达7，000美元的效益）。这一净效应严重制约了受影响地区奶制品和牛肉部门以及绵羊和山羊饲养业的增长和发展。由于缺乏疫苗的现实前景，杀锥虫药物是控制AAT的主要药物。病媒控制取得的成功有限，而且可持续性差，在非采采蝇传播很重要的地区（例如非洲部分地区，但特别是在远东和南美洲）更是如此，全球牲畜兽医联盟（GALVmed）的成立是为了帮助引导全球努力，减轻各种传染病给世界粮食安全带来的负担。在英国国际发展部和比尔及梅林达·盖茨基金会的大量资助下，GALVmed已成为参与开发治疗AAT新药的主要机构。在这项提案中，格拉斯哥大学和斯特拉斯克莱德大学以及爱丁堡大学罗斯林研究所的专家，正在共同开发一类新的化合物，该化合物已被证明在体外和啮齿动物疾病模型中对AAT的病原体具有深刻的功效。将开发针对牛中杀锥虫活性优化的这些化合物的化学结构，旨在将其纳入临床开发。我们还将为相关寄生虫物种开发新的培养系统-这是快速和常规筛选候选药物的关键一步，也是大量不相关化合物（化学库）的关键一步，最大限度地减少了动物试验的需要。我们还将使用最先进的生物学和计算方法来了解致病寄生虫的内部功能，以了解这类新化合物的工作原理。该项目的这一部分还将提供关键信息，允许其他类别的化合物被提出，为治疗AAT的新药的长期管道提供重要的投入。

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.