Novel Treatment Could Combat Deadly Nerve Agents

A modified enzyme helps neutralize the effects of organophosphorus (OP) agents, responsible for the deaths of hundreds of thousands of people worldwide every year.

Researchers at the Russian Academy of Sciences (RAS; Moscow, Russia), Moscow State University (Russia), the University of Sheffield (United Kingdom), and other institutions used recombinant chemical surface modification (polysialylation) to generate bioscavengers that are both stable in the bloodstream and possess enhanced pharmacokinetics. The bioscavenger enzymes were able to protect mice against the nerve agent VR (4.2 LD50 of S-(2-(diethylamino)ethyl) O-isobutyl methanephosphonothioate),without disruption of long-term behavior.

The researchers used a modified human enzyme to develop the bioscavenger, using combination of polysialylation and biotechnology of production, through the use of an in vitro CHO-based expression system that employs genes encoding butyrylcholinesterase (BChE, a nonspecific cholinesterase enzyme that hydrolyses many different choline esters) and a proline-rich peptide constructed with a special elongation factor promoter control. The result was self-assembling, active enzyme multimers. The study describing the production of the modified enzyme was published early online on January 7, 2013, in the journal Proceeding of the National Academy of Sciences of the United States of America (PNAS).

“This current publication describes a novel method to generate a bioscavenger for the Russian VR organophosphorus agent with the key property of being long-acting in the bloodstream,” said study coauthor Prof. Mike Blackburn, PhD, from the University of Sheffield’s department of molecular biology and biotechnology, who served as a consultant on the project.

OPs include compounds like Tabun, which was developed in 1936 by German scientists during World War II, Sarin, Soman, Cyclosarin, VX, and VR. Many OPs are used as pesticides in developing countries, and acute poisoning is common because of insufficient control, poor storage, ready availability, and inadequate education amongst farmers. It is estimated about 200,000 people die each year across the world from OP poisoning through occupational exposure, unintentional use, and misuse, mostly in developing countries like India, Pakistan, and Sri Lanka, and through deliberate terrorist activities.

Related Links:
Russian Academy of Sciences
Moscow State University
University of Sheffield