Citation

Vayron P, Renard PY, Taran F, Créminon C, Frobert Y, Grassi J, Mioskowski C. Proc. Natl. Acad. Sci. U. S. A. 2000; 97(13): 7058-7063.

Affiliation

CEA, Service des Molécules Marquées, DBCM, and Service de Pharmacologie et d'Immunologie, DRM, CE Saclay 91191, Gif sur Yvette Cedex, France.

Copyright

(Copyright © 2000, National Academy of Sciences)

DOI

unavailable

PMID

10860971

PMCID

PMC16498

Abstract

We report here our preliminary results on the use of catalytic antibodies as an approach to neutralizing organophosphorus chemical weapons. A first-generation hapten, methyl-alpha-hydroxyphosphinate Ha, was designed to mimic the approach of an incoming water molecule for the hydrolysis of exceedingly toxic methylphosphonothioate VX (1a). A moderate protective activity was first observed on polyclonal antibodies raised against Ha. The results were further confirmed by using a mAb PAR 15 raised against phenyl-alpha-hydroxyphosphinate Hb, which catalyzes the hydrolysis of PhX (1b), a less toxic phenylphosphonothioate analog of VX with a rate constant of 0.36 M(-1) x min(-1) at pH 7.4 and 25 degrees C, which corresponds to a catalytic proficiency of 14,400 M(-1) toward the rate constant for the uncatalyzed hydrolysis of 1b. This is a demonstration on the organophosphorus poisons themselves that mAbs can catalytically hydrolyze nerve agents, and a significant step toward the production of therapeutically active abzymes to treat poisoning by warfare agents.

Language: en