Two proteins, human plasma BuChE, and a recombinant human BuChE are both in advanced development as potential prophylacitcs for proteting aginst chemical warfare agents. These proteins react rapidly and stoiciometrically to effectively scavenge the poisons in the blood stream but they require relatively large amounts of protein to provide protection. The challenge of identifying a protein based drug that would require less material while providing improved protection with the advantage of enhanced user acceptance cannot be ignored. Recent efforts in our laboratory have identified human paraoxonase (PON) as a protein that can catalyze the hydrolysis of all nerve agents and as a naturally occuring plasma enzyme should have an in vivo bioavailability of hours or days. As such it is an excellent candidate for phrophylactic administration to provide protection for first responders to a terorist attack or military forces in a civilian peacekeeping setting subject to an asymmetric threat. If it were administered intravenously it could also serve as a rapid-onset therapeutic antidote to a segment of the civilian popuation exposed to nerve agents. Preliminary studies have shown that these objectives are both feasible and obtainable. The cost/benefit ratio of such a drug is such that it is an excellent candidate for success and has the potential to be the first in a series of a novel class of drugs. We propose to use rational design to identify those amino acids critical for cataltyic activity and then, using site directe mutagenesis, enhance the native catalytic activity of human PON to create a viable candidate for transition to advancement to clinical trials within a five year period. This will address a critical gap in the national goal of protecting the civilian population against a terrorist-initiated chemical weapons attack. Current medical protection against chemical nerve agent exposure by terrorists is limited to post exposure treatment. We will identify and develop for clinical testing a human protein capable of providing rapid and long lasting prophylactic protection against exposure to chemical warfare nerve agents. Such a drug will address the critical national goal of providing improved protection to the general population against a terrorist-initiated chemical weapons attack.