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

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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.