Oxime-Conjugated Dendrimers as Therapeutics for Organophosphate Poisoning

Abstract

Organophosphates (OPs) are a class of organophosphorus compounds which have a general structure of O=P(OR)3. Paraoxon (also known as POX) is an organophosphate found in insecticides often used in agriculture in impoverished countries. OPs are also used in nerve gas agents such as Sarin gas, used in warfare.These molecules are extremely toxic and can be lethal at low doses. Organophosphates negatively impact the body’s neurotransmitter enzyme, acetylcholinesterase. Muscle spasms, paralysis, narrowed pupils, glossy eyes, confusion, and the over-secretion of bodily fluids such as sweat, saliva, mucus, and tears, are symptoms of organophosphate poisoning (Fletcher, 2017). To reduce the harmful effects from this organic compound, we have designed and screened dendrimer nanoparticles modified with poly (ethylene glycol) chains and with small reactor molecules. Dendrimers are synthetic macromolecules, which contain chains of repeated, branching molecules that form a tree-like or snowflake-like structure. Dendrimers can be used to enhance permeability in drug delivery. There are many active sites attached to small reactor molecules on the dendrimer branches, allowing for the successful and efficient inactivation of POX before penetrating the skin (Mukherjee, 2015). The second focus of our experiment was to screen for hundreds of oxime molecules that most effectively reactivate acetylcholinesterase. Oxime molecules are an organic imine compound that can be used to detach the toxic OPs from acetylcholinesterase. OP’s bind to Ser200 on the enzyme, leading to inactivation. Oxime molecules bind in a nucleophilic attack to the phosphorus on organophosphate, causing it to diffuse away from the enzyme. This paper highlights the two focuses of our experiment: 1. Perform enzyme assays to screen for the best compounds at reactivating acetylcholinesterase, and 2. Attach oxime molecules at the branching sites of dendrimers to enhance permeability into the subdermal layer of the skin. We have identified some potential oxime molecules and dendrimers to be complexed and used as a treatment for OP poisoning or incorporated into a cream-based drug product to protect those at high risk of exposure to organophosphates.