Pharmacological prevention of 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