MICA: Modes of action and resistance mechanisms towards anti-trypanosomal benzoxaboroles

人类非洲锥虫病（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。这些微生物是通过采采蝇传播的，采采蝇吸食人类血液，并在吸食人类血液时注入寄生虫。寄生虫最初在血液中增殖，但随后侵入中枢神经系统。寄生虫在大脑中增殖的存在导致神经功能的进行性崩溃，包括睡眠-觉醒模式的改变，这使得这种疾病有了一个共同的名字。由于多种原因，目前可用于HAT的药物不能令人满意。一种化合物，美拉胂醇，是以砷为基础的，毒性很大，每20个接受这种药物治疗的人中就有一个死于这种药物。另一种化合物，称为依氟鸟氨酸，必须通过滴注注入静脉，每天几次，持续两周（或一周，如果与另一种称为硝呋莫司的药物联合使用（硝呋莫司本身就是一种潜在的致癌剂！）。目前急需新药，两种化合物正在临床试验中。一种叫做非昔硝唑的药物正在由被忽视疾病药物倡议（DNDi）开发，目前正在进行II期临床试验。第二种化合物，目前在第一阶段试验是SCYX-7158，由DNDi与Anacor和Scynexis联合开发的苯并氧杂硼杂环戊烯类化合物之一。虽然fexinidazole是一种硝基杂环化合物，其活性取决于它被锥虫体内发现的酶激活，但对苯并氧杂硼杂环的作用机制知之甚少。它们是一类非常新颖的化合物。然而，清楚的是，在已经产生的数百种关于这个主题的变体中，它们似乎并不都以相同的方式工作，这是基于杀死寄生虫所需的时间以及这些化合物所针对的寄生虫的外观的一些差异。在这里，我们建议使用各种最先进的技术来确定苯并氧杂硼杂环戊烯类的不同成员如何工作。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性机制，这将使我们能够将它们分类为不太可能发生交叉耐药性的组。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种致命疾病的时期内推动抗锥虫药物开发的管道。

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.