Enzyme inhibitors as a novel treatment for snake venom induced necrosis (360G-Wellcome-211450_Z_18_Z)

Snakebite is a neglected tropical disease that causes both systemic (~125,000 fatalities per annum) and local (up to 500,000 cases of long-term morbidity) toxicities. Snakebite therapy, known as antivenom, is highly ineffective at treating the local tissue destructive effects of snake venom, as antivenom antibodies are poor at crossing the blood-tissue barrier. In this project I will assess the validity of neutralising necrotic snake venoms with an alternative approach - enzyme inhibitors, which will target the toxin families (snake venom metalloproteinases and phospholipases A2) known to cause local tissue destruction. To do so, I will screen a range of small molecules that have been licensed as human medicines or demonstrated to be safe in clinical trials, to facilitate rapid translation. I will first use in-house, small-scale, biochemical assays to characterise the metalloproteinase and phospholipase activity of ten known necrotic venoms, before assessing the neutralising capability of the inhibitors in the same assays. Next, I will use matrigel as a substrate representing the basement membrane extracellular matrix for degradation based assessments. The results of these assays will identify the optimal combination of anti-necrosis enzyme inhibitors that can be taken forward into preclinical assessments of in vivo venom neutralisation in the future.