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

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。它是由一种名为锥虫的微小单细胞寄生虫引起的。这些生物是由采采蝇传播的，采采蝇吸人血，并在吸血时注入寄生虫。寄生虫最初在血液中繁殖，但随后入侵中枢神经系统。寄生虫在大脑中扩散的存在会导致神经功能的进行性崩溃，包括睡眠-觉醒模式的改变，这就是这种疾病的俗称。由于一些原因，目前可用于HAT的药物不能令人满意。一种名为美拉索洛尔的化合物是以砷为基础的，毒性极大，以至于每20名接受药物治疗的人中就有一人因服用该药物而死亡。另一种名为依氟鸟氨酸的化合物必须通过静脉注射，每天几次，持续两周(如果与另一种名为硝呋莫司(Nifurtimox)的药物联合使用则为一周)。迫切需要新药，目前有两种化合物正在进行临床试验。一种名为费西硝唑的药物正由被忽视疾病药物倡议(DNDI)开发，目前处于第二阶段临床试验。目前处于第一阶段试验的第二种化合物是SCYX-7158，它是DNDI与Anacor和Scynexis联合开发的苯并恶硼醇类化合物之一。虽然非辛硝唑是一种被称为硝基杂环化合物的化合物，其活性依赖于锥虫体内发现的一种酶的激活，但人们对苯并恶环化合物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，在这个主题的数百种变体中，根据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，它们似乎并不都以相同的方式起作用。在这里，我们建议使用各种最先进的技术来准确确定苯并恶硼化合物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，从而使化学家能够开发出更有效的抑制剂。此外，我们还将了解药物耐药的机制，这将使我们能够将它们归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期间，为抗锥虫药物的开发提供燃料。

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.