Title
Peripheral site ligand conjugation to a non-quaternary oxime enhances reactivation of nerve agent-inhibited human acetylcholinesterase
Author
de Koning, M.C.
van Grol, M.
Noort, D.
Publication year
2011
Abstract
Commonly employed pyridinium-oxime (charged) reactivators of nerve agent inhibited acetylcholinesterase (AChE) do not readily pass the blood brain barrier (BBB) because of the presence of charge(s). Conversely, non-ionic oxime reactivators often suffer from a lack of reactivating potency due to a low affinity for the active site of AChE. It was therefore hypothesized that an extra contribution in affinity may be achieved by covalently connecting a peripheral site ligand (PSL) to a non-ionic reactivator, which may result in a higher reactivation potency of the total construct. This validity of this approach, which proved successful for charged pyridinium oximes in earlier work, is now further exemplified with the covalent linkage of a neutral PSL via a spacer to a non-ionic and otherwise almost non-reactivating a-ketoaldoxime. It is demonstrated that the linkage of the PSL resulted in a remarkable increase in reactivation potency of the hybrid compounds. Although the molecules reported here are still inefficient reactivators compared to the current pyridinium oximes, the presented approach holds promise for the future design and synthesis of non-ionic oxime reactivators with improved BBB penetration and may be suited as well for non-oxime reactivators thus further widening the scope in the ongoing search for broad-spectrum reactivators. © 2011 Elsevier Ireland Ltd.
Subject
Life
CBRN - CBRN Protection
EELS - Earth, Environmental and Life Sciences
Acetylcholinesterase
Nerve agent
Non-quaternary oxime
Peripheral site
Reactivation
4 methoxyphenyl oxo ethanaloxime
Acetylcholinesterase
Cholinesterase reactivator
Oxime
Pyridinium derivative
Unclassified drug
Article
Binding affinity
Blood brain barrier
Drug conjugation
Drug inhibition
Drug structure
Drug synthesis
Electrospray mass spectrometry
Enzyme active site
High performance liquid chromatography
Liquid chromatography
Priority journal
Purification
Chemicals/CAS: acetylcholinesterase, 9000-81-1
To reference this document use:
http://resolver.tudelft.nl/uuid:ee45977c-10f3-4682-ac3f-db4b1d230739
DOI
https://doi.org/10.1016/j.toxlet.2011.04.004
TNO identifier
435961
ISSN
0378-4274
Source
Toxicology Letters, 206 (1), 54-59
Document type
article