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
• 负责人: Mike Barrett
• 金额: $ 79.69万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL018853%2F1
• 关键词: MICA; Modes; action; resistance; mechanisms

Human African trypanosomiasis (HAT), often known as sleeping sickness, is a disease found primarily in rural Africa. It is caused by tiny single celled parasites called trypanosomes. These organisms are transmitted by tsetse flies which suck human blood and can inject parasites while doing so. The parasites initially proliferate in blood but then invade the central nervous system. The presence of parasites proliferating in the brain causes a progressive breakdown in neurological functioning, including alterations in sleep-wake patterns which lend the disease its common name. Drugs that are currently available for HAT are unsatisfactory for a number of reasons. One compound, melarsoprol, is based on arsenic and is so toxic that one in every twenty people treated with the drug die as a result of its administration. Another compound, called eflornithine, has to be injected into veins through a drip several times a day for a fortnight (or a week if given in combination with another drug called nifurtimox (which itself is a potential cancer-causing agent!). New drugs are urgently needed and two compounds are currently in clinical trials. One, called fexinidazole, is being developed by the Drugs for Neglected Diseases initiative (DNDi) and is currently in phase II clinical trials. The second compound, now in Phase I trials is SCYX-7158, one of the benzoxaborole class of compound developed by DNDi in conjunction with Anacor and Scynexis. Whilst fexinidazole is what is known as a nitroheterocyclic compound, whose activity depends on its being activated by an enzyme found inside trypanosomes, little is known about how benzoxaboroles work. They are a very novel class of compound. What is clear, however, is that of the hundreds of variations on this theme that have been produced, they appear not to all work in the same way, based on the time it takes to kill parasites and some differences in the appearance of parasites targeted by these compounds. Here we propose to use a variety of state-of-the-art technologies to determine exactly how different members of the benzoxaborole class work. We will find enzymatic targets of these drugs which will then enable chemists to develop even more potent inhibitors. Moreover, we will also learn about mechanisms of resistance to the drugs which will allow us to classify them into groups where cross resistance is unlikely to occur. Our ultimate aim is to learn as much as possible about this class of compound with a view to fuelling the pipeline of anti-trypanosomal drug development during a period dedicated to the elimination and possibly even eradication of this fatal disease.

非洲人类锥虫病（HAT），通常被称为昏睡病，是一种主要在非洲农村发现的疾病。它是由微小的单细胞寄生虫锥虫引起的。这些生物通过采采蝇传播，采采蝇吸人血，并在吸人血的同时注入寄生虫。寄生虫最初在血液中繁殖，然后侵入中枢神经系统。寄生虫在大脑中大量繁殖，导致神经功能逐渐崩溃，包括睡眠-觉醒模式的改变，这也是该疾病常见名称的由来。由于一些原因，目前可用于HAT的药物不能令人满意。其中一种化合物，褪黑胂醇，是以砷为基础的，它的毒性很大，每20个接受这种药物治疗的人中就有一个死于服用这种药物。另一种叫做依氟鸟氨酸的化合物必须每天滴注几次静脉，持续两周（如果与另一种叫做硝呋替莫的药物联合使用，则需要一周）。迫切需要新的药物，目前有两种化合物正在临床试验中。一种名为非昔硝唑的药物正在由被忽视疾病药物计划（DNDi）开发，目前正在进行II期临床试验。第二种正在进行I期临床试验的化合物是SCYX-7158，是由DNDi与Anacor和Scynexis联合开发的苯并恶罗洛类化合物之一。虽然非昔硝唑是一种已知的硝基杂环化合物，其活性取决于它被锥虫体内发现的一种酶激活，但人们对苯并恶硼唑的工作原理知之甚少。它们是一类非常新颖的化合物。然而，有一点是明确的，在这一主题的数百种变体中，它们似乎并不都以同样的方式起作用，这是基于杀死寄生虫所需的时间和这些化合物所针对的寄生虫外观的一些差异。在这里，我们建议使用各种最先进的技术来确定苯并恶波罗类的不同成员是如何工作的。我们将找到这些药物的酶靶点，这将使化学家能够开发出更有效的抑制剂。此外，我们还将了解对药物的耐药机制，这将使我们能够将它们分类为不太可能发生交叉耐药的组。我们的最终目标是尽可能多地了解这类化合物，以期在致力于消除甚至可能根除这一致命疾病的时期促进抗锥虫药物开发的管道。

项目成果

Determination of antiprotozoal drug mechanisms by metabolomics approaches.

• DOI: 10.1017/s0031182013000814
• 发表时间: 2014-01
• 期刊: Parasitology
• 影响因子: 2.4
• 作者: Creek DJ;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: PLoS pathogens
• 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

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: PLoS pathogens
• 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