A Discovery and Development Pipeline for Cyanide Countermeasures

氰化物是典型的化学威胁。这种强大的天然毒素在许多不同的环境中都会遇到，潜在的暴露范围从工业事故到重大恐怖袭击。氰化物具有毁灭性的后果。较高的剂量会迅速导致癫痫发作、心血管衰竭和死亡，而较低的剂量则会导致大量的长期发病率，包括使人衰弱的中枢神经系统损伤。目前可用的解毒剂根本不符合潜在的大规模伤亡威胁场景的复杂性或规模，迫切需要开发新的对策。该卓越建议的主要目标是1）在经过验证的斑马鱼模型系统中使用无偏方法识别新型氰化物对策，2）在体内探索这些新对策类的构效关系（SAR），并使用药物化学产生一系列优化的先导化合物; 3）以在已建立的氰化物毒性的鼠和兔模型中验证这些优化的先导化合物。 这些跨学科的目标集中在U 54合作申请的总体目标上：确定至少3种新型氰化物对策，以便在当前申请完成时直接进入正式的临床前测试和I期临床研究。 使用该管道成功生成三种经过验证的对策，不仅为临床前开发中的并行工作奠定基础，（通过CounterACT临床前开发机构或CPDF，如下所述）以及这些化合物的后续临床开发（当前提案的逻辑延伸），而且还将形成一种可推广的方法，以加速制定针对任何现有或新出现的化学威胁的对策。

Cyanide is an archetypal chemical threat. This powerful natural toxin is encountered in many different settings and potential exposures range from industrial accidents to major terrorist attacks. Cyanide has devastating consequences. Higher quantities lead rapidly to seizures, cardiovascular collapse and death, while lower doses are associated with substantial long-term morbidity including debilitating central nervous system injury. Currently available antidotes simply do not match the complexity or scale of the potential mass casualty threat scenarios, and there is an urgent need to develop novel countermeasures. The major aims of this CounterACT Center of Excellence proposal are 1) to identify novel classes of cyanide countermeasure using unbiased approaches in a validated zebrafish model system, 2) to explore in vivo the structure activity relationships (SAR) of these novel countermeasure classes and using medicinal chemistry generate a series of optimized lead compounds and 3) to validate these optimized leads in established murine and rabbit models of cyanide toxicity. Together these individual interdisciplinary aims are focused around the overarching goal of this collaborative U54 application: The identification of at least 3 novel cyanide countermeasures ready to move directly to formal preclinical testing and Phase I clinical studies at the completion of the current application. Successful generation of three validated countermeasures using this pipeline will not only lay the foundation for parallel work in preclinical development (through the CounterACT Preclinical Development Facility or CPDF as outlined below) and for subsequent clinical development of these compounds (in a logical extension of the current proposal), but will also form a generalizable approach for the accelerated development of countermeasures to any existing or emerging chemical threat.