Mechanisms of acetylcholinesterase protection against sarin and soman by adenosine A1 receptor agonist N6-cyclopentyladenosine
| Autor: | Tsung-Ming Shih, Thaddeus P. Thomas, Ariana Beste, DeCarlos E. Taylor |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Agonist medicine.drug_class Pharmacology 010402 general chemistry 01 natural sciences Biochemistry 03 medical and health sciences chemistry.chemical_compound Adenosine A1 receptor Structural Biology Soman medicine heterocyclic compounds Enzyme Reactivation Nerve agent N6-Cyclopentyladenosine Organic Chemistry Acetylcholinesterase 0104 chemical sciences Computational Mathematics 030104 developmental biology chemistry cardiovascular system Cholinergic medicine.drug |
| Zdroj: | Computational Biology and Chemistry. 75:74-81 |
| ISSN: | 1476-9271 |
| Popis: | Organophosphorus nerve agents (NAs) irreversibly inhibit acetylcholinesterase (AChE), the enzyme responsible for breaking down the neurotransmitter acetylcholine (ACh). The over accumulation of ACh after NA exposure leads to cholinergic toxicity, seizure, and death. Current medical countermeasures effectively mitigate peripheral symptoms, however; the brain is often unprotected. Alternative acute treatment with the adenosine A1 receptor agonist N6-cyclopentyladensosine (CPA) has previously been demonstrated to prevent AChE inhibition as well as to suppress neuronal activity. The mechanism of AChE protection is unknown. To elucidate the feasibility of potential CPA-AChE interaction mechanisms, we applied a truncated molecular model approach and density functional theory. The candidate mechanisms studied are reversible enzyme inhibition, enzyme reactivation, and NA blocking prior to enzyme conjugation. Our thermodynamic data suggest that CPA can compete with the NAs sarin and soman for the active site of AChE, but may, in contrast to NAs, undergo back-reaction. We found a strong interaction between CPA and NA conjugated AChE, making enzyme reactivation unlikely but possibly allowing for CPA protection through the prevention of NA aging. The data also indicates that there is an affinity between CPA and unbound NAs. The results from this study support the hypothesis that CPA counters NA toxicity via multiple mechanisms and is a promising therapeutic strategy that warrants further development. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect