Catalytic Approach to Treatment of Cyanide Poisoning

描述(由申请人提供)：这份R21申请概述了一种通过在血液中代谢氰化物而不是使用肝脏中的罗丹酶来催化并快速从体内清除氰化物的方法。氰化物的加速生物消除是通过给予带有聚合物结合的半胱氨酸的催化剂来实现的，该催化剂可迅速与氰化物反应生成惰性硫氰酸盐，从而对抗氰化物的毒性。使用原型化合物的初步结果表明，在生理pH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一种毒素，很容易被用于自杀、杀人和战争。它在工业上用于熏蒸、电镀和采矿等任务，意外接触可能会危及生命。对氰化物中毒进行有效的大规模治疗对公共健康、防御和促进吸入性损伤的康复至关重要。鉴于氰化物对人类健康和环境的潜在影响，几个国际组织已将其列为优先化学品。肝脏中氰化物代谢的天然底物会随着人体对氰化物的过度吸收而迅速耗尽。硫代硫酸盐在肝脏中的溶解度有限，导致反应缓慢，同时促进了硫烷硫向若丹明的转移。这里提出的是通过催化剂将硫催化转移到血流中与聚合物结合的半胱氨酸，该半胱氨酸将形成活性半胱氨酸，并与氰化物快速反应。将在体外和体内筛选关键化合物的毒性和有效性。这项工作的长期目标是开发一种适合肌肉内(IM)给药的催化解毒疗法。小剂量是IM开发工作成功的关键，而催化解毒是小剂量的关键。肌注比静脉注射更容易进行，因此适合于大量伤员的快速治疗或自我给药。该机制的优点是：(1)剂量小；毒性风险低；(2)血浆溶解度；(3)高生物利用度；(4)肌注给药。这项工作的具体目标是：(1)开发作为硫烷硫转移剂的钼硫化合物；(2)开发一种无毒的半胱氨酸聚合物，具有脂和血浆溶解度平衡和高半胱氨酸负载量；(3)进行活性研究，以确定一种新的硫供体，能够在20分钟或更短的时间内将90%+的氰化物转化为硫氰酸盐；(4)进行催化系统的体外疗效研究，以及(5)在动物模型上进行体内疗效研究，以证明与羟钴胺(Cyanokit(Tm))同等或更好的疗效，羟钴胺每种治疗方法每名患者5至20克。 与公众健康相关：这项研究建议开发一种催化解毒疗法，以快速从血液中清除氰化物，而不是通过肝脏。氰化物中毒的存活率很低，因为这种毒药见效快，治疗选择有限。氰化物在建筑火灾中是一种严重的健康危害，也是一种工业危险，目前还缺乏有效的大规模氰化物中毒处理方法。

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.