A new drug discovery pipeline for animal African trypanosomiasis

治疗非洲动物锥虫病的新药研发管线

基本信息

  • 批准号:
    BB/N007999/1
  • 负责人:
  • 金额:
    $ 75.47万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2016
  • 资助国家:
    英国
  • 起止时间:
    2016 至 无数据
  • 项目状态:
    已结题

项目摘要

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.
非洲大陆承担着世界传染病(人类和兽医)的不成比例的负担。在最具破坏性的动物传染因子中,是引起非洲动物锥虫病(AAT)的锥虫。该病主要由采采蝇和其他叮咬蝇传播,存在于40个非洲国家,影响几乎所有家畜。每年可归因于AAT的整体经济损失估计为47.5亿美元。这些损失主要由负担能力最低的人承担:撒哈拉以南非洲大部分受aat影响地区的小规模自给农民和农村社区,他们依靠牲畜为生。目前的AAT控制工具广泛依赖锥虫药物来治疗受感染的动物和预防感染。这些药物可广泛获得,但它们是50多年前开发的,在安全性方面存在重大局限性,并且对新出现的耐药锥虫越来越缺乏疗效。非洲有超过1000万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,数以百万计的小规模牲畜饲养者依靠约5500万头牛和7000万只绵羊和山羊维持生计和粮食安全。这些地区面临着持续不断的压力,需要为不断增长的人口生产更多的粮食,肉类和乳制品的人均消费量不断增加,气候变化和荒漠化都要求撒哈拉以南非洲潜在生产地区增加农业产量。AAT造成的损失既有直接损失(例如,估计每年有300万头牛死亡),也有因生产力损失而造成的间接损失(例如,清除AAT每平方公里可获得高达7 000美元的收益)。净影响是对受影响地区乳制品和牛肉部门的增长和发展以及绵羊和山羊饲养的重大制约。由于疫苗缺乏现实的前景,锥虫药物是控制AAT的主要手段。病媒控制取得的成功有限,可持续性较差,在非采采蝇传播重要的地区更是如此(例如非洲部分地区,但特别是在远东和南美洲)。全球畜牧兽医联盟(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已成为研发治疗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们正在共同开发一种新型化合物,这种化合物在体外和啮齿动物疾病模型中都被证明对AAT的病原体具有深远的功效。这些化合物的化学结构将被优化,用于牛的锥虫杀灭活性,目的是将其用于临床开发。我们还将为相关的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以及大量不相关化合物(化学文库)的关键一步,而不需要进行动物试验。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,以了解这种新型化合物是如何工作的。该项目的这一部分还将提供关键信息,以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输入。

项目成果

期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Halogenated tryptophan derivatives disrupt essential transamination mechanisms in bloodstream form Trypanosoma brucei.
卤素色氨酸衍生物破坏了血液中的基本跨跨机制,形成了锥虫瘤。
  • DOI:
    10.1371/journal.pntd.0008928
  • 发表时间:
    2020-12
  • 期刊:
  • 影响因子:
    3.8
  • 作者:
    Cockram PE;Dickie EA;Barrett MP;Smith TK
  • 通讯作者:
    Smith TK
Truncated S-MGBs: towards a parasite-specific and low aggregation chemotype.
  • DOI:
    10.1039/d1md00110h
  • 发表时间:
    2021-08-18
  • 期刊:
  • 影响因子:
    4.1
  • 作者:
    Brooke DP;McGee LMC;Giordani F;Cross JM;Khalaf AI;Irving C;Gillingwater K;Shaw CD;Carter KC;Barrett MP;Suckling CJ;Scott FJ
  • 通讯作者:
    Scott FJ
Diminazene resistance in Trypanosoma congolense is not caused by reduced transport capacity but associated with reduced mitochondrial membrane potential
  • DOI:
    10.1111/mmi.14733
  • 发表时间:
    2021-05-18
  • 期刊:
  • 影响因子:
    3.6
  • 作者:
    Carruthers, Lauren, V;Munday, Jane C.;De Koning, Harry P.
  • 通讯作者:
    De Koning, Harry P.
Veterinary trypanocidal benzoxaboroles are peptidase-activated prodrugs.
兽医苯唑替洛尔斯是肽酶激活的前药。
  • DOI:
    10.1371/journal.ppat.1008932
  • 发表时间:
    2020-11
  • 期刊:
  • 影响因子:
    6.7
  • 作者:
    Giordani F;Paape D;Vincent IM;Pountain AW;Fernández-Cortés F;Rico E;Zhang N;Morrison LJ;Freund Y;Witty MJ;Peter R;Edwards DY;Wilkes JM;van der Hooft JJJ;Regnault C;Read KD;Horn D;Field MC;Barrett MP
  • 通讯作者:
    Barrett MP
The trypanocidal benzoxaborole AN7973 inhibits trypanosome mRNA processing.
  • DOI:
    10.1371/journal.ppat.1007315
  • 发表时间:
    2018-09
  • 期刊:
  • 影响因子:
    6.7
  • 作者:
    Begolo D;Vincent IM;Giordani F;Pöhner I;Witty MJ;Rowan TG;Bengaly Z;Gillingwater K;Freund Y;Wade RC;Barrett MP;Clayton C
  • 通讯作者:
    Clayton C
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Mike Barrett其他文献

Just the Facts: Assessing and managing soft tissue knee injuries in the Emergency Department
  • DOI:
    10.1007/s43678-024-00761-w
  • 发表时间:
    2024-08-10
  • 期刊:
  • 影响因子:
    2.000
  • 作者:
    Benjamin Gompels;Luke McCarron;Luka Jovanovic;Thomas Molloy;Vazeer Ahmed;Martin Gargan;Mike Barrett
  • 通讯作者:
    Mike Barrett
Optoelectronic tweezers for medical diagnostics
用于医疗诊断的光电镊子
  • DOI:
  • 发表时间:
    2012
  • 期刊:
  • 影响因子:
    0
  • 作者:
    C. Kremer;S. Neale;A. Menachery;Mike Barrett;J. Cooper
  • 通讯作者:
    J. Cooper

Mike Barrett的其他文献

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{{ truncateString('Mike Barrett', 18)}}的其他基金

Metabolism and drug resistance probed with new genetic tools in the neglected animal pathogen Trypanosoma vivax.
用新的遗传工具探讨了被忽视的动物病原体间日锥虫的代谢和耐药性。
  • 批准号:
    BB/W000431/1
  • 财政年份:
    2022
  • 资助金额:
    $ 75.47万
  • 项目类别:
    Research Grant
Bridging epigenetics, metabolism and cell cycle in pathogenic trypanosomatids
连接致病性锥虫的表观遗传学、代谢和细胞周期
  • 批准号:
    MR/S019650/1
  • 财政年份:
    2019
  • 资助金额:
    $ 75.47万
  • 项目类别:
    Research Grant
An integrated approach to tackling drug resistance in livestock trypanosomes.
解决家畜锥虫耐药性的综合方法。
  • 批准号:
    BB/S001034/1
  • 财政年份:
    2019
  • 资助金额:
    $ 75.47万
  • 项目类别:
    Research Grant
MICA: Modes of action and resistance mechanisms towards anti-trypanosomal benzoxaboroles
MICA:抗锥虫苯并氧杂硼化合物的作用方式和耐药机制
  • 批准号:
    MR/L018853/1
  • 财政年份:
    2014
  • 资助金额:
    $ 75.47万
  • 项目类别:
    Research Grant
The Silicon Trypanosome
硅锥虫
  • 批准号:
    BB/I004599/1
  • 财政年份:
    2010
  • 资助金额:
    $ 75.47万
  • 项目类别:
    Research Grant
Metabolomic systems biology analysis of differentiation in trypanosomes
锥虫分化的代谢组学系统生物学分析
  • 批准号:
    BB/F005679/1
  • 财政年份:
    2008
  • 资助金额:
    $ 75.47万
  • 项目类别:
    Research Grant

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