Tandon Researcher Engineering Antidotes to Chemical Weapons

antidotes
A molecule of the highly neurotoxic agent VX attaching to the binding pocket of phosphotriesterase (PTE)

Chemical weapons and other toxic agents including pesticides pose a serious health threat worldwide, whether they are deliberately released or emitted by accident from industrial chemical operations during processing, shipping, or storage.

Jin Montclare, an associate professor in the Department of Chemical and Biomolecular Engineering at the NYU Tandon School of Engineering is participating in a U.S. government program to thwart these agents by improving upon compounds known to neutralize them. Montclare was awarded a grant by the U.S. government’s CounterACT (Countermeasures Against Chemical Threats) program under the National Institutes of Health, which supports research to prevent and treat exposure.

The $349,040 grant furthers Montclare’s work on phosphotriesterase (PTE), a compound that can deactivate the neurotoxic agent organophosphorus, the active compound in a number of pesticides and a rogue’s gallery of chemical warfare agents like VX, the most toxic nerve agent ever created that is considered a weapon of mass destruction. As was demonstrated in the assassination this year of Kim Jong-nam, the half-brother of North Korea’s leader, a fraction of a drop of VX absorbed through the skin is fatal.

When this enzyme is blocked, toxic accumulation of acetylcholine in the synapses between neurons and muscle cells follows, resulting in hyper-stimulation of neural pathways, in turn causing ataxia (loss of muscle control), coma, convulsions, and death. Even with expedient treatment, which involves administering a cocktail of atropine, oximes and benzodiazepines, mortality rates are as high as 40 percent. V-series agents like VX, VR, VM, and Sarin — used in the IranIraq War during the 1980s, in attacks in Japanese cities by the Aum Shinrikyo cult in the 1990s, and by the Syrian government on its citizens in 2013 — work by inhibiting the enzyme acetylcholinesterase (AChE), which catalyzes the breakdown of acetylcholine and other neurotransmitters.

PTE’s activity varies considerably from agent to agent and it possesses a short half-life. Montclare’s research is aimed at creating variants that are stable, robust and effective in neutralizing a plethora of toxic chemical agents.

Montclare’s work, in collaboration with Dr. Tamara Otto at the U.S. Army Medical Research Institute of Chemical Defense (USAMRICD) at the Aberdeen Proving Ground, takes a two-pronged approach to modifying PTE: The researchers incorporated a protein/fluorine complex into PTE that confers stability and longer half-life; and, with Richard Bonneau, Director of the NYU Center for Data Science, they are using computational biology software suite Rosetta, which includes algorithms for modeling and analysis of protein structures, to re-engineer PTE’s active receptor site to “recognize” and bind more easily with a variety of V-agents.

Bonneau explains, “This work really represents an ideal application of computational protein design. We are really excited to work to make new design codes that mesh well with the bioengineering side of this project.”

Montclare said the team will use experimental results to investigate a second-generation set of fluorinated-PTE variants.

“This feedback-based approach will allow us to refine Rosetta to improve specific activity for the V-agents, making fluorinated-PTE variants even more effective based on insights from activity and stability data,” she said.

Montclare published her first paper on methods of synthesizing stable PTE in 2011, with a focus on detoxifying pesticides, research in which she is still engaged through a collaboration with the United States Food and Drug Administration.

Source : NYU Tandon School of Engineering