Toward antibody-catalyzed hydrolysis of organophosphorus poisons

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-␣-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-␣-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 ⅐min ؊1 at pH 7.4 and 25°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.

Research and Development of On-site Decontamination System for Biological and Chemical Warfare Agents

“…99) The antibodies possessing hydrolytic activity toward nerve gases are reported. 100) Enzymatic methods for decontaminating not only CWAs but also BWAs are summarized by Richardt and Blum. 101) Kantogakuin University (Prof. Kawahara) and NRIPS investigated the decomposing power against nerve gases using Flavobacterium OPH.…”

Design and Synthesis of anα,α-Difluorophosphinate Hapten for Antibody-Catalyzed Hydrolysis of Organophosphorus Nerve Agents

“…[ 13] Here we describe the synthesis of a second-generation hapten which is charged and mimics the transition state of another hydrolysis pathway.…”

“…PhX reversibly inhibits AChE with a 20 nm IC 50 , [13] whereas VX (1) almost irreversibly inhibits AChE with a 0.2 nm IC 50 (intravenous Abstract in French: Dans cet article, nous deÂcrivons la syntheÁse de lhapteÁne 6, de structure a,a-difluorophosphinate. Cet hapteÁne est destine aÁ eÃtre utilise dans une nouvelle approche pour neutraliser les agents de guerre chimiques organophosphoreÂs, graÃce aÁ des anticorps aÁ activite catalytique de type phosphatase.…”

Incorporation of ethical and societal issues in biochemistry into a senior seminar course

“…In several sentences each, the students are asked to respond to the following. [12] Trinucleotide repeat disorders [13] Gene replacement, gene therapy, and ethics [14][15][16] Ribozymes [17] Functional genomics [18] Protein structure/function Prions [19] Protein structure and genomics, ethical considerations [20,21] Metalloproteinase inhibitors [22] Catalytic antibodies [23] Apoptosis/cancer/AIDS Apoptosis [24] Telomerase [25] Clinical resistance to cancer therapy [26] HIV therapy [27] Neurochemistry Long term potentiation [28] Alzheimer's disease [29] Drugs of abuse [10,30] Psychological disorders [11] 4. Describe any ethical issues or societal concerns that are raised in the paper.…”