Two proteins, human plasma BuChE, and a recombinant human BuChE are both in advanced developmentas potential prophylacitcs for proteting aginst chemical warfare agents. These proteins react rapidly andstoiciometrically to effectively scavenge the poisons in the blood stream but they require relatively largeamounts of protein to provide protection. The challenge of identifying a protein based drug that wouldrequire less material while providing improved protection with the advantage of enhanced user acceptancecannot be ignored. Recent efforts in our laboratory have identified human paraoxonase (PON) as a proteinthat can catalyze the hydrolysis of all nerve agents and as a naturally occuring plasma enzyme should havean in vivo bioavailability of hours or days. As such it is an excellent candidate for phrophylactic administrationto provide protection for first responders to a terorist attack or military forces in a civilian peacekeepingsetting subject to an asymmetric threat. If it were administered intravenously it could also serve as a rapid-onsettherapeutic antidote to a segment of the civilian popuation exposed to nerve agents. Preliminarystudies have shown that these objectives are both feasible and obtainable. The cost/benefit ratio of such adrug is such that it is an excellent candidate for success and has the potential to be the first in a series of anovel class of drugs. We propose to use rational design to identify those amino acids critical for cataltyicactivity and then, using site directe mutagenesis, enhance the native catalytic activity of human PON tocreate a viable candidate for transition to advancement to clinical trials within a five year period. This willaddress a critical gap in the national goal of protecting the civilian population against a terrorist-initiatedchemical weapons attack.Current medical protection against chemical nerve agent exposure by terrorists is limited to post exposuretreatment. We will identify and develop for clinical testing a human protein capable of providing rapid andlong lasting prophylactic protection against exposure to chemical warfare nerve agents. Such a drug willaddress the critical national goal of providing improved protection to the general population against aterrorist-initiated chemical weapons attack.
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