Catalytic bioscavengers against organophosphorus agents: mechanistic issues of self-reactivating cholinesterases

Catalytic bioscavengers are the second-generation bioscavengers. These biopharmaceuticals are intended to degrade toxic organophosphorus agents on the skin for decontamination or in the bloodstream for pre-treatment and post-exposure treatment of organophosphate poisoning. Because catalytic degradation has to be fast, their catalytic efficiency has to be as high as possible (k_cat/K_m>10⁶ M^-1 min^-1). Certain evolved mammalian paraoxonases and bacterial phosphotriesterases already fulfill this requirement. To be of interest, the catalytic activity of certain enzymes has to be increased by several orders of magnitude. This can be reached by computer-redesign or directed evolution existing enzymes, and alternatively, combinational strategies. The present paper focuses on the better understanding of catalytic mechanisms of cholinesterase inhibition, aging and reactivation and how this knowledge serves the rational design of novel catalytic bioscavengers based on cholinesterase structure.