Catalytic Approach to Treatment of Cyanide Poisoning

描述（由申请人提供）：该R21申请概述了一种通过代谢血液中的氰化物而不是使用肝脏中的罗丹酶来催化和快速去除体内氰化物的方法。氰化物的加速生物消除是通过施用具有聚合物结合的半胱氨酸的催化剂来实现的，所述半胱氨酸快速与氰化物反应以产生惰性硫氰酸盐，从而拮抗氰化物毒性。使用原型化合物的初步结果表明，在生理pH值下的筛选反应中，氰化物转化为惰性产物硫氰酸盐。氰化物中毒迅速，治疗选择有限。氰化物越来越被认为是建筑火灾中的毒素，并且很容易用于自杀，杀人和战争。它在工业上用于熏蒸、电镀和采矿等任务，意外接触可能危及生命。氰化物中毒的有效大规模治疗对于公共卫生，防御和改善吸入性损伤的恢复至关重要。几个国际组织已将氰化物指定为对人类健康和环境具有潜在影响的优先化学品。肝脏中氰化物代谢的天然底物随着氰化物的过度吸收而迅速耗尽。硫代硫酸盐在肝脏中有限的溶解度导致反应缓慢，同时促进硫烷硫转移到罗丹酸。这里提出的是通过催化剂将催化硫转移到血流中的聚合物结合的半胱氨酸，这将形成与氰化物快速反应的活化半胱氨酸。将在体外和体内筛选关键化合物的毒性和功效。这项工作的长期目标是开发一种适合肌内（IM）给药的催化解毒治疗。小剂量是IM开发工作成功的关键，催化解毒是小剂量的关键。IM比静脉（IV）注射更容易执行，因此适合于大量伤员的快速治疗或自我给药。提出的机制的优点是：（1）小剂量;毒性风险较低;（2）血浆溶解度，（3）高生物利用度，和（4）IM给药。本工作的具体目标是（1）开发氘-硫化合物以催化充当硫烷硫转移剂;（2）开发具有脂质和血浆溶解度平衡和高半胱氨酸负载的无毒含半胱氨酸聚合物;（3）进行反应性研究以鉴定能够在20分钟或更短时间内将90%+的氰化物转化为硫氰酸盐的新型硫供体;（4）进行催化系统的体外功效研究，和（5）在动物模型中进行体内功效研究，以证明与Hydroxocobalamin（CyanokitTM）相比相等或更好的功效，Hydroxocobalamin（CyanokitTM）为5 - 20 g/患者/治疗。 公共卫生相关性：这项研究建议开发一种催化解毒治疗方法，以快速从血液中去除氰化物，而不是通过肝脏。氰化物中毒的存活率很低，因为毒药是快速作用的，治疗方案有限。氰化物在建筑火灾中是一种严重的健康危害，也是一种工业危害，目前缺乏有效的氰化物中毒群众治疗方法。

DESCRIPTION (provided by applicant): This R21 application outlines an approach to catalytically and rapidly remove cyanide from the body by metabolizing the cyanide in the bloodstream rather than using the rhodanese enzyme in the liver. The accelerated bioelimination of cyanide is accomplished by administration of a catalyst with a polymer-bound cysteine that rapidly reacts with cyanide to produce inert thiocyanate, thereby antagonizing cyanide toxicity. Preliminary results using a prototype compound demonstrate conversion of cyanide into the inert product, thiocyanate, in a screening reaction at physiological pH. Cyanide poisoning is rapid and treatment options are limited. Cyanide is increasingly recognized as a toxin in building fires and is easily accessible for use in suicides, homicides, and warfare. It is used industrially in tasks such as fumigation, electroplating, and mining, and accidental exposure can be life-threatening. An efficient mass treatment for cyanide poisoning is essential for public health, counter-defense, and improving recovery for inhalation injuries. Several international organizations have designated cyanide a priority chemical in terms of its potential impact on human health and the environment. The natural substrates for cyanide metabolism in the liver become depleted rapidly with excessive absorption of cyanide into the body. Thiosulfate's limited solubility in the liver leads to a slow reaction while facilitating sulfane sulfur transfer to rhodanese. Proposed here is catalytic sulfur transfer by a catalyst to a polymer-bound cysteine in the bloodstream, which will form an activated cysteine that reacts rapidly with cyanide. Key compounds will be screened for toxicity and efficacy in vitro and in vivo. The long-term goal of this work is to develop a catalytic detoxification treatment suitable for intramuscular (IM) administration. A small dose is key to the success of an IM development effort, and catalytic detoxification is key to a small dose. IM is easier to perform than intravenous (IV) injection and therefore suitable for rapid treatment of large numbers of casualties or for self-administration. The advantages of the proposed mechanism are: (1) small dose; lower risk of toxicity; (2) plasma solubility, (3) high bioavailability, and (4) IM administration. The specific aims for this work are to (1) develop molybdenum-sulfur compounds to catalytically serve as sulfane sulfur transfer agents; (2) develop a non-toxic cysteine-bearing polymer that has a balance of lipid and plasma solubility and high cysteine loading; (3) conduct reactivity studies to identify a novel sulfur donor able to convert 90%+ of the cyanide to thiocyanate in 20 min or less; (4) conduct in vitro efficacy studies of a catalytic system, and (5) perform in vivo efficacy studies in an animal model to demonstrate equal or better efficacy compared to Hydroxocobalamin (Cyanokit(tm)), which is 5 to 20 g per patient per treatment. PUBLIC HEALTH RELEVANCE: This study proposes to develop a catalytic detoxification treatment to rapidly remove cyanide from the bloodstream rather than by way of the liver. The survival rate from cyanide poisoning is low because the poison is fast-acting and treatment options are limited. Cyanide is a serious health hazard in building fires and as an industrial hazard, and an efficient mass treatment for cyanide poisoning is lacking.