Medical Aspects of Chemical Warfare (2008) - The Black Vault

Nerve Agent Bioscavenger: Development of a New Approach to Protect Against Organophosphorus Exposuredirected mutations in Hu PON1, the lack of knowledgeon the residues at the active site and the enzyme’sthree-dimensional structure, were recently overcomeby the work of Josse et al, 65,66 Harel et al, 77 Aharoni etal, 78 and Yeung et al. 79,80 Based on site-directed mutationsof amino acids believed to be at or near the activesite of Hu PON1 and on limited sequence homologywith a DFPase, Josse et al had postulated that the moleculehad the shape of a 6-fold beta propeller. Usinga mouse-rat-rabbit-human chimera of paraoxonase1 obtained through gene shuffling experiments andexpressed in bacteria, Harel et al 77 and Aharoni et al 78confirmed the postulated structure through X-raycrystallographic studies. Yeung et al have subsequentlycarried out site-directed mutation studies to identifyand “map” amino acid residues critical for binding andinvolved in catalytic activity. 79,80 Further studies haverevealed a degree of stereospecificity in the hydrolysisof soman by native Hu PON1, with the least toxic somanstereoisomer (C+P+) being hydrolyzed ~ 6 timesmore efficiently than the most toxic one (C−P−). 81 Theobserved stereospecificity is primarily due to preferentialbinding rather than to enhanced turnover of the(C+P+) stereoisomer by Hu PON1. All of these recentfindings support the goal of designing a recombinantversion of a naturally occurring human enzyme thatcan be developed as a catalytic biological scavenger toprotect against nerve agent poisoning.INTERAGENCY PARTNERSHIPS: PROJECT BIOSHIELDProject BioShield was signed into law by PresidentGeorge W Bush on July 21, 2004. It grants the secretariesof the US Department of Health and HumanServices and the US Department of Homeland Securityauthority to present the president and the director ofthe US Office of Management and Budget with recommendationsfor developing and procuring countermeasuresto chemical, biological, radiological, and nuclearthreats. Funding over 10 years was appropriated tothe Department of Homeland Security for Project Bio-Shield, establishing a new spending authority to spurdevelopment and procurement of “next generation”medical countermeasures (vaccines, therapeutics, anddiagnostics) against chemical, biological, radiological,and nuclear agents. It also authorizes the National Institutesof Health to speed research and developmentin promising areas of medical countermeasures tothese agents, grants increased flexibility and authorityto award contracts and grants under expedited peerreview procedures, and allows more rapid hiring oftechnical experts deemed necessary for research anddevelopment efforts. The Department of Defense isjoining in this effort to leverage interagency resources.The objectives are to develop dual-use technologiesand products that can be used to expand target populations(military and civilians) for US Food and DrugAdministration licensure. Project BioShield legislationrequires that products are manufactured under currentGood Manufacturing Practices (practices recognizedworld-wide that ensure the safe manufacturing, management,testing, and control of goods, foods, andpharmaceuticals) and have completed a successfulPhase I human clinical safety trial. Plasma-derived HuBChE is currently being produced from human CohnFraction IV-4 and will be used for preclinical safetyand toxicology testing with the intention of large-scaleproduction and more extensive testing to be carried outleading to licensure. The bioscavenger countermeasurehas been identified as a potential candidate for ProjectBioShield.Collaborating in the BioShield process requires theDepartment of Defense to expand the concept of useto first responders, healthcare workers, and civilians.One way to protect those groups may be to stockpilesufficient amounts of pHu BChE, which could then beused in conjunction with extensive decontaminationmeasures and personal protective equipment whenindicated. In some settings, pHu BChE may replacethe need for pyridostigmine bromide as a pretreatmentmedical countermeasure. Most studies tested theenzyme as a preventive countermeasure because oncethe nerve agent has reached the nerve synapse, pHuBChE becomes ineffective; at that point, interventionwould include the traditional countermeasures (atropine,pralidoxime, and anticonvulsant). Although themajority of bioscavenger use will be in the preexposuresetting, bioscavenger may also be useful in neutralizingon-going postexposure risks following skin absorption,which could lead to prolonged systemic exposure (ie,the “depot effect”).SUMMARYOP nerve agents represent a very real threat notonly to service members in the field but also to thepublic at large. Nerve agents have already been usedby terrorist groups against civilians and, because oftheir low cost and relative ease of synthesis, are likelyto be used again in the future. In addition, many commonlyused pesticides and chemical manufacturingby-products can act as anticholinesterases and may251