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Engineered Protein Detoxes Pesticides, Chemical Weapons

Jim Kim Montclare

Jim Kim Montclare (New York University)

1 August 2014. Biochemists at New York University synthesized a protein that removes the toxic elements of chemicals found in pesticides and some chemical warfare agents. The team led by Jin Kim Montclare at NYU’s engineering school published its findings last week in the journal ChemBioChem (paid subscription required).

The process, which includes use of computational modeling software, produces a synthesized protein that removes the toxicity of organophosphates, compounds found in many commercial pesticides and sarin, a nerve agent considered a weapon of mass destruction under international law. Organophosphates limit enzymes regulating a chemical in the nervous system called acetylcholine that carries signals between nerves and muscles. Without that regulating capability, acetylcholine builds up in the nerves, resulting in paralysis of muscles, including respiratory muscles, leading to suffocation and death.

Montclare and colleagues — including Richard Bonneau, a biology and computer science professor at NYU — engineered enzymes called phosphotriesterases, which in their natural state have properties that degrade organophosphates. But also in their natural state, phosphotriesterases are unstable; they easily lose their potency and breakdown under high temperatures.

The researchers thus sought a way of improving the stability of phosphotriesterases, while maintaining their ability to act on organophosphates. “We’ve known that phosphotriesterases had the power to detoxify these nerve agents,” says Montclare in a university statement, “but they were far too fragile to be used therapeutically.”

The NYU team turned to Rosetta, software for molecular modeling of protein structures that offers algorithms for analyzing molecular interactions and designing custom molecules. The researchers used Rosetta to identify mutations in fluoridated forms of phosphotriesterases, which they knew from earlier studies improved the protein’s folding, where amino acids in proteins take the shape that specifies their functions.

The mutations revealed through Rosetta improved the stability of phosphotriesterases even further, with one variation identified as pFF-F104A shown able to work at higher temperatures, and with enough stability to continue working for many days at room temperature. The university filed a provisional patent for the process that includes the computational design of the synthesized protein.

Montclare says the engineered protein can be the basis for therapies for farm workers overexposed to pesticides or victims of nerve gas attacks. It can also be formulated into chemicals for cleaning up or decommissioning chemical weapons stores that now require heat and caustic chemicals. “These proteins could accomplish that same task enzymatically,” notes Montclare, “without the need for reactors and formation of dangerous byproducts.”

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