Pharmacological prevention of snake venom cytotoxicity

蛇毒细胞毒性的药理学预防

• 批准号: 2117777
• 金额: --
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2117777
• 关键词: Pharmacological; prevention; snake; venom; cytotoxicity

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

这个学生将解决一个未满足的临床需求，开发新的疗法来治疗蛇毒液，并研究由Bothrops物种蛇毒引起的细胞毒性的细胞机制。这个项目是与C教授合作的。Chavez Olortegui（巴西米纳斯吉拉斯联邦大学）、艾德泰特教授（帝国理工学院化学系）和阿斯利康。蛇咬伤事故给发展中国家最贫穷的人口造成了严重负担。大多数蛇咬伤发生在农业工人中，毒液可导致从危及生命的全身性障碍到复杂的局部组织损伤的症状，这些症状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存在许多局限性。特别是，通常严重的局部影响很难被抗蛇毒中和。这些影响在临床上很重要，因为它们可能导致永久性残疾。这种情况往往由于病人需要长期住院和康复而更加严重，这可能大大推迟他们恢复健康和经济生产生活的时间。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，以及（ii）识别和验证旨在改善咬伤部位严重组织破坏的药物，作为蛇咬伤患者的快速有效的药理学治疗。已确定的药物将补充主要对循环毒素有效的抗蛇毒疗法。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（与许多抗蛇毒血清所见的有限的跨物种中和作用相反）。总的来说，这种方法可以成为改善医疗和解决目前世界范围内抗蛇毒血清短缺问题的重要途径。此前，该实验室成功地鉴定了FDA批准的抑制Bothrops毒素（或毒液）细胞作用的药物的特定子集。学生将从这些发现中建立并解决以下问题：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。第二，药物的身份与机理数据一起将有助于选择库，以与阿斯利康的共同监督人J沃尔什和H.Plant一起搜索更活性和更有效的化合物。其目的是产生新的额外的药效团的起点，除了FDA产生的铅靶向Bothrops毒液的细胞毒性。阿斯利康提供的合适的库是临床化合物库（患者准备好耐受性和有效性的证据）和临床前库（药物优化，旨在帮助探索途径和疾病生物学机制）。此外，这样的筛选可以通过可用的表型筛选集（针对细胞中的已知活性选择）以及由计算输入驱动的设计子集来补充