Developing a Bioscavenger Against Organophosphate Nerve Agents (original) (raw)

Reed B. Jacob: Developing a bioscavenger against organophosphate nerve agents (Under the direction of Nikolay V. Dokholyan) Organophosphate poisoning can occur from exposure to agricultural pesticides or chemical weapons. This exposure inhibits acetylcholinesterase resulting in increased acetylcholine levels within the synaptic cleft causing loss of muscle control, seizures, and death. Mitigating the effects of organophosphates in our bodies is critical and yet an unsolved challenge. Weaponized organophosphates are a deadly threat to armed forces and civilians (e.g., exposure to one droplet of VX exceeds the LD50 of ~15 μg/kg). Here, we present two computational strategies to 1) identify a novel protein acting as a stoichiometric bioscavenger to covalently bind organophosphates, and 2) improve the stability and activity of organophosphate hydrolase as a catalytic bioscavenger through allosteric modulation. We use our first computational strategy, integrating structure mining and modeling approaches, to identify novel candidates capable of interacting with a serine hydrolase probe (either covalently or with equilibrium binding constants ranging from 20 to 120 µM). One candidate Smu. 1393c catalyzes the hydrolysis of the organophosphate omethoate (kcat/Km of (2.0±1.3)×10-1 M-1 s-1) and paraoxon (kcat/Km of (4.6±0.8)×10 3 M-1 s-1), V-and G-agent analogs respectively. In addition, Smu. 1393c protects acetylcholinesterase activity from being inhibited by two organophosphate simulants. We demonstrate that the utilized approach is an efficient and

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