Pharmacological prevention of snake venom cytotoxicity

该项目旨在解决目前尚未满足的临床需求，开发治疗蛇中毒的新疗法，并研究由Bothrops物种的蛇毒引起的细胞毒性的细胞机制。该项目由C. Chavez Olortegui教授（巴西米纳斯吉拉斯州联邦大学）、Ed Tate教授（帝国理工学院化学系）和阿斯利康合作完成。蛇咬伤事故给发展中国家最贫穷的人口造成了严重的负担。大多数蛇咬伤发生在农业工人中，中毒可导致各种症状，从危及生命的全身性紊乱到复杂的局部组织损伤，可导致永久性毁容和截肢。抗蛇毒血清是目前唯一有效的治疗方法，但在确保患者完全康复方面有许多限制。特别是，通常严重的局部影响很难被抗蛇毒血清中和。这些影响在临床上很重要，因为它们可能导致永久性残疾。这种情况往往由于患者需要长期住院和康复而变得更加复杂，这可能大大推迟他们恢复健康和经济上有生产力的生活。该学生将研究(i)强烈破坏细胞功能导致组织损伤的特定毒素，（ii）识别和验证旨在改善咬伤部位严重组织破坏的药物，作为对蛇咬伤患者的快速有效的药物治疗。确定的药物将补充抗蛇毒治疗，主要是有效的循环毒素。最重要的是，潜在的合适药物可能能够改善由不同蛇毒引起的中毒症状（与许多抗蛇毒所见的有限的跨物种中和相反）。总的来说，这种方法可能是改善医疗和解决目前全球抗蛇毒血清短缺问题的重要途径。此前，该实验室成功鉴定了fda批准的抑制Bothrops毒素（或毒液）细胞作用的药物的特定亚群。学生将以这些发现为基础，解决以下问题：首先，选定药物的潜在细胞作用机制和表型筛选，以剖析所涉及的途径。其次，药物的特性和机制数据将有助于选择文库，在阿斯利康的共同主管J Walsh和H.Plant的帮助下，搜索更有效的活性化合物。目的是除了fda生成的针对Bothrops毒液细胞毒性的先导外，产生新的额外药效团起点。阿斯利康可用的合适文库是临床化合物库（患者已准备好耐受性和有效性的证据）和临床前工具箱（药理学优化，旨在帮助探索途径和疾病生物学机制）。此外，这种筛选可以通过可用的表型筛选集（选择已知细胞活性）以及由计算输入驱动的设计子集来补充

This studentship will address an unmet clinical need to develop novel therapies to treat snake envenomation and investigate the cellular mechanisms of cytoxicity caused by snake venom from Bothrops species. This project is a collaboration with Prof C. Chavez Olortegui (Federal University of Minas Gerais, Brazil), Prof Ed Tate (Dept Chemistry, Imperial College) and AstraZeneca. Snakebite accidents poses a severe burden on the poorest populations of developing countries. Most snakebites occur among agricultural workers and envenoming can result in symptoms ranging from systemic, life-threatening disturbances to a complex local tissue damage that can lead to permanent disfigurement and amputations. Anti-venom is currently the only effective therapy available, but has a number of limitations in securing full recovery of patients. In particular, the often severe local effects are poorly neutralized by anti-venoms. These effects are clinically important as they can cause permanent disability. This scenario is often compounded by the need for prolonged hospitalization and rehabilitation of the patients that can markedly delay their return to a healthy and economically productive life. The student will investigate (i) the specific toxins that strongly disrupt cellular function leading to tissue damage and (ii) identify and validate drugs designed to ameliorate severe tissue destruction at the bite site as a fast and effective pharmacological treatment for snakebite patients. The identified drugs will complement anti-venom therapy that is effective primarily against circulating toxins. Most importantly, potentially suitable drugs may be able to ameliorate envenoming symptoms caused by different snake venoms (in contrast to the limited cross-species neutralization seen with many anti-venoms). Overall, this approach could represent an important way of improving medical treatment and addressing the current worldwide shortage of anti-venoms. Previously, the lab successfully identified specific subsets of FDA-approved drugs that inhibit the cellular action of Bothrops toxins (or venom). The student will build from these findings and address the following: first, the potential cellular mechanisms of action of selected drugs and phenotypic screens to dissect the pathways involved. Second, the identity of the drug(s) together with the mechanistic data will help to select libraries to search more active and effective compounds with co-supervisors J Walsh and H.Plant at AstraZeneca. The aim is to generate new additional pharmacophore starting points in addition to the FDA-generated leads targeting cytoxicity of Bothrops venoms. Suitable libraries available at AstraZeneca are the Clinical Compound Bank (patient ready with evidence of tolerability and efficacy) and Preclinical Toolbox (pharmacologically optimised and intended to help explore pathways and disease biology mechanisms). In addition, such screens can be complemented by available phenotypic screening set (selected for known activity in cells) as well as designed subsets driven by computational input