Synthetic Developments for the Treatment of Organophosphorus Nerve Agent Poisoning
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2016
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ndltd-OhioLink-oai-etd.ohiolink.edu-osu14609714992021-08-03T06:35:45Z Synthetic Developments for the Treatment of Organophosphorus Nerve Agent Poisoning Young, Amneh Chemistry Acetylcholinesterase (AChE) is a serine hydrolase responsible for the hydrolysis of the neurotransmitter acetylcholine. It hydrolyzes over 25,000 acetylcholine (ACh) molecules every second. Inhibition of AChE catalytic site results in muscle contractions, blurry vision, seizures, and respiratory failure. Organophosphorus (OP) compounds are potent inhibitors of the enzyme AChE. Once the OP enters the enzyme active site, it phosphylates a serine residue (Ser203) to give an irreversibly inhibited AChE that is incapable of hydrolyzing ACh. This leads to a buildup of ACh at cholinergic receptors and constant stimulation of nerve fibers. Reactivation of AChE can occur by hydrolysis of the phosphylated enzyme which is usually accomplished by use of a nucleophilic oxime, such as 2-PAM, often administered after OP exposure as a treatment. However, if reactivation does not occur, the phosphylated enzyme will then undergo a spontaneous dealkylation process (called aging) to give an aged enzyme which, to date, cannot be reactivated.This dissertation covers multiple strategies to combat OP poisoning. First is the design of a pre-treatment in the form of catalytic antibodies capable of hydrolyzing OPs before they can inhibit AChE. The potential for antibodies to catalyze hydrolysis reactions inspired several reports of abzyme neutralization of OP nerve agents. To produce the catalytic antibodies, our group designed and synthesized a small library of haptens that mimic the transition state of nerve agent hydrolysis. These haptens are then conjugated to an immunogenic protein and antibodies are raised that hopefully hydrolyze nerve agents before they can inhibit AChE. Ten haptens were synthesized and preliminary results indicate that these haptens either bind or hydrolyze our target OP nerve agent.The second approach is the use of a cyclic peptide to mimic the active site of known OP bioscavengers. A combinatorial approach was used to develop a library of peptides synthesized on a bead using common solid phase peptide chemistry. A novel screening approach will be discussed. The final strategy is the design of quinone methide precursors (QMPs) that will enter the active site of AChE and alkylate the “aged” enzyme. Once alkylated, AChE can be reactivated using a nucleophilic oxime (2-PAM). Our goal is to design QMPs which will bind to and selectively alkylate aged AChE. We designed four different families of QMPs that can be easily accessed via simple transformations of commercially available starting materials. An undergraduate organic chemistry lab experiment was designed to aid in the synthesis of the QMP library and produced over 100 QMPs in gram quantities. Approximately half of the QMPs react with model nucleophiles under physiological conditions. The reactivity of these QMPs with model phosphonylated peptides and aged AChE will be discussed. 2016-09-23 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1460971499 http://rave.ohiolink.edu/etdc/view?acc_num=osu1460971499 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
| collection |
NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Chemistry |
| spellingShingle |
Chemistry Young, Amneh Synthetic Developments for the Treatment of Organophosphorus Nerve Agent Poisoning |
| author |
Young, Amneh |
| author_facet |
Young, Amneh |
| author_sort |
Young, Amneh |
| title |
Synthetic Developments for the Treatment of Organophosphorus Nerve Agent Poisoning |
| title_short |
Synthetic Developments for the Treatment of Organophosphorus Nerve Agent Poisoning |
| title_full |
Synthetic Developments for the Treatment of Organophosphorus Nerve Agent Poisoning |
| title_fullStr |
Synthetic Developments for the Treatment of Organophosphorus Nerve Agent Poisoning |
| title_full_unstemmed |
Synthetic Developments for the Treatment of Organophosphorus Nerve Agent Poisoning |
| title_sort |
synthetic developments for the treatment of organophosphorus nerve agent poisoning |
| publisher |
The Ohio State University / OhioLINK |
| publishDate |
2016 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=osu1460971499 |
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