Gurevitz Michael, Karbat Izhar, Cohen Lior, Ilan Nitza, Kahn Roy, Turkov Michael, Stankiewicz Maria, Stühmer Walter, Dong Ke, Gordon Dalia
Department of Plant Sciences, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Ramat-Aviv 69978, Tel-Aviv, Israel.
Toxicon. 2007 Mar 15;49(4):473-89. doi: 10.1016/j.toxicon.2006.11.015. Epub 2006 Nov 28.
Voltage-gated sodium channels are a major target for toxins and insecticides due to their central role in excitability, but due to the conservation of these channels in Animalia most insecticides do not distinguish between those of insects and mammals, thereby imposing risks to humans and livestock. Evidently, as long as modern agriculture depends heavily on the use of insecticides there is a great need for new substances capable of differentiating between sodium channel subtypes. Such substances exist in venomous animals, but ways for their exploitation have not yet been developed due to problems associated with manufacturing, degradation, and delivery to the target channels. Engineering of plants for expression of anti-insect toxins or use of natural vectors that express toxins near their target site (e.g. baculoviruses) are still problematic and raise public concern. In this problematic reality a rational approach might be to learn from nature how to design highly selective anti-insect compounds preferably in the form of peptidomimetics. This is a complex task that requires the elucidation of the face of interaction between insect-selective toxins and their sodium channel receptor sites. This review delineates current progress in: (i) elucidation of the bioactive surfaces of scorpion beta-toxins, especially the excitatory and depressant groups, which show high preference for insects and bind insect sodium channels with high affinity; (ii) studies of the mode of interaction of scorpion beta-toxins with receptor site-4 on voltage-gated sodium channels; and (iii) clarification of channel elements that constitute receptor site-4. This information may be useful in future attempts to mimic the bioactive surface of the toxins for the design of anti-insect selective peptidomimetics.
电压门控钠通道因其在兴奋性方面的核心作用,成为毒素和杀虫剂的主要作用靶点。但由于这些通道在动物界具有保守性,大多数杀虫剂无法区分昆虫和哺乳动物的通道,从而给人类和牲畜带来风险。显然,只要现代农业严重依赖杀虫剂的使用,就迫切需要能够区分钠通道亚型的新物质。这类物质存在于有毒动物体内,但由于制造、降解以及向靶通道递送等相关问题,尚未开发出利用它们的方法。通过工程手段使植物表达抗昆虫毒素,或使用在其靶位点附近表达毒素的天然载体(如杆状病毒)仍然存在问题,并引起公众关注。在这种充满问题的现实情况下,一种合理的方法可能是向自然界学习如何设计高度选择性的抗昆虫化合物,最好是以拟肽的形式。这是一项复杂的任务,需要阐明昆虫选择性毒素与其钠通道受体位点之间的相互作用情况。本综述阐述了以下方面的当前进展:(i)阐明蝎β毒素的生物活性表面,特别是对昆虫具有高度偏好并以高亲和力结合昆虫钠通道的兴奋性和抑制性基团;(ii)研究蝎β毒素与电压门控钠通道上受体位点4的相互作用模式;(iii)阐明构成受体位点4的通道元件。这些信息可能有助于未来模仿毒素的生物活性表面来设计抗昆虫选择性拟肽。