Developing high-throughput screens for nematocides

家畜继续受到蛔虫(线虫)寄生虫的困扰，给加拿大农民和牧场主造成了经济损失。对这些寄生虫最好的防御是小分子抗寄生虫药(杀线虫)，其中几种在市场上。然而，寄生虫总是对成功的、因此被广泛使用的药物产生抗药性，限制了它们的疗效。预见到对新一代杀线虫化合物的需求，我们已经确定了线虫特有的神经递质受体家族。受体是一个乙酰胆碱门控氯通道家族(ACCs)。我们已经证明，激活至少一种受体蛋白(ACC-1)形成的通道的药物应该对蠕虫是致命的。在目前的提案中，我们试图识别其他致命性的ACC受体，并开发一种有效的方法来筛选激活AcCs的化合物的大型化学库。这种先导化合物将被开发成一种安全的驱虫药物，不太可能对现有药物产生抗药性。

Livestock continue to be plagued by roundworm (nematode) parasites causing economic losses to Canadian farmers and ranchers. The best defense against these parasites are small molecule antiparasitic drugs (nematocides), several of which are on the market. However, parasites invariably acquire resistance to successful, and thus widely used drugs, limiting their efficacy. Anticipating the need for a new generation of nematocidal compounds, we have identified a family of neurotransmitter receptors that are unique to nematodes. The receptors are a family acetylcholine-gated chloride channels (ACCs). We have shown that a drug that activates the channels formed by at least one of the receptor proteins (ACC-1) should be lethal to worms. In the current proposal we seek to identify other lethal ACC receptors and develop an efficient method to screen large chemical libraries for compounds that activate the the ACCs. Such a lead compound would be developed into a safe deworming drug that would be less likely to suffer from resistance already developed against existing drugs.