Human Paraoxonase Bioscavenger for Nerve Agents

In this Phase I, Agave BioSystems proposes to develop a catalytic organophosphorus bioscavenger based on human paraoxonase 1 (PON1) for the protection of personnel against OP nerve agents. A catalytic bioscavenger that detoxifies multiple organophosphorus (OP) molecules by hydrolysis rather than a single OP molecule like Hu-BuChE greatly reduces the amount of protein required, making administration of the scavenger to large numbers of individuals safer and less expensive. PON1 is a serum protein found in humans and other animals which has been shown to catalytically inactivate paraoxon and other organophosphorus compounds. While the wild type human enzyme possesses too little activity to protect against large doses of OP agents, preliminary studies of chimeric PON1 mutants have identified a number of sequence changes that increase phosphotriesterase (PTE) activity significantly. A human PON1 (huPON1) with enhanced PTE activity could provide full protection against otherwise lethal exposures to OP agents and would still be compatible with the human immune system, allowing multiple doses to be administered.