Design and Production of Peptides Mimicking the Active Site of Serine Esterases with Covalent Binding to the Organophosphorus Poison Soman

摘要

The objective of this research program was to design, synthesize and test mimics of acetylcholinesterase (AChE), the natural target of soman, that would scavenge the organophosphate poison soman in vivo and thereby provide protection against this chemical warfare agent. During this program, compounds were developed that were active in vitro, affording protection to AChE, and active in vivo, affording protection against lethality to guinea pigs. The naturally occurring Beta-cyclodextrin Beta CD was shown to scavenge soman invitro .001 M, thus affording protection to AChE; covalent bonding was demonstrated by no reversibility of scavenging and by the isolation of Beta CD-soman adducts. Functional modifications introduced on the narrow primary rim of Beta CD were generally without effect in improving activity. Substituents introduced on the more open, secondary rim of Beta CD resulted in diminished activity. Dramatic improvement in scavenging was achieved with a Beta CD that was rigidly capped on the primary rim. The most active compound tested in vitro was also active in vivo, affording a protection ratio of greater than 1.5 in guinea pigs at a 20 mg dose. Higher dosing to afford protection against multiple LD50's should be possible for this compound because of the low toxicity of cyclodextrins. This compound and analogs based on it should be pursued further. (AW)