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Biomolecules
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The Role of Cholinesterases in Alzheimer’s Disease and Other Neurodegenerative...
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The Role of Cholinesterases in Alzheimer’s Disease and Other Neurodegenerative Disorders

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Natural and Bio-inspired Molecules".

Deadline for manuscript submissions: 30 September 2024 | Viewed by 1144

Special Issue Editor

Prof. Dr. Sultan Darvesh

E-Mail Website
Guest Editor
Departments of Medicine (Neurology and Geriatric Medicine) and Medical Neuroscience, Dalhousie University, Halifax, NS B3H 4R2, Canada
Interests: Alzheimer's disease; diagnostic and therapeutic agents for dementia; acetylcholinesterase; butyrylcholinesterase; neurodegenerative disease; neuroimaging; medicinal chemistry; enzyme kinetics; cognitive neurology; brain banking
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

I am serving as Guest Editor for the Special Issue “The Role of Cholinesterases in Alzheimer’s Disease and Other Neurodegenerative Disorders” in Biomolecules (https://www.mdpi.com/journal/biomolecules). I would be pleased if you would agree to contribute a research paper or review on any aspect related to the theme of “The Role of Cholinesterases in Alzheimer’s Disease and Other Neurodegenerative Disorders”. Below you will find some information that you may find useful when considering this invitation.

In this Special Issue we would like to explore the various aspects of acetylcholinesterase and butyrylcholinesterase, including both enzymatic and non-enzymatic functions, to try and consolidate available information and ascertain how this focus may inform future research toward an understanding of the underlying causes of Alzheimer’s disease and other neurodegenerative disorders. In turn, this could help elucidate more effective disease-modifying and diagnostic approaches for these conditions.

Prof. Dr. Sultan Darvesh
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Alzheimer’s disease
  • acetylcholinesterase
  • butyrylcholinesterase
  • enzymatic properties
  • non-enzymatic properties
  • neuroinflammation
  • drug development
  • neuroimaging

Published Papers (2 papers)

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Research

37 pages, 9291 KiB  
Article
New Heterostilbene and Triazole Oximes as Potential CNS-Active and Cholinesterase-Targeted Therapeutics
by Milena Mlakić, Tena Čadež, Goran Šinko, Irena Škorić and Zrinka Kovarik
Biomolecules 2024, 14(6), 679; https://doi.org/10.3390/biom14060679 - 11 Jun 2024
Viewed by 273
Abstract
New furan, thiophene, and triazole oximes were synthesized through several-step reaction paths to investigate their potential for the development of central nervous systems (CNS)-active and cholinesterase-targeted therapeutics in organophosphorus compound (OP) poisonings. Treating patients with acute OP poisoning is still a challenge despite [...] Read more.
New furan, thiophene, and triazole oximes were synthesized through several-step reaction paths to investigate their potential for the development of central nervous systems (CNS)-active and cholinesterase-targeted therapeutics in organophosphorus compound (OP) poisonings. Treating patients with acute OP poisoning is still a challenge despite the development of a large number of oxime compounds that should have the capacity to reactivate acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The activity of these two enzymes, crucial for neurotransmission, is blocked by OP, which has the consequence of disturbing normal cholinergic nerve signal transduction in the peripheral and CNS, leading to a cholinergic crisis. The oximes in use have one or two pyridinium rings and cross the brain–blood barrier poorly due to the quaternary nitrogen. Following our recent study on 2-thienostilbene oximes, in this paper, we described the synthesis of 63 heterostilbene derivatives, of which 26 oximes were tested as inhibitors and reactivators of AChE and BChE inhibited by OP nerve agents–sarin and cyclosarin. While the majority of oximes were potent inhibitors of both enzymes in the micromolar range, we identified several oximes as BChE or AChE selective inhibitors with the potential for drug development. Furthermore, the oximes were poor reactivators of AChE; four heterocyclic derivatives reactivated cyclosarin-inhibited BChE up to 70%, and cis,trans-5 [2-((Z)-2-(5-((E)-(hydroxyimino)methyl)thiophen-2-yl)vinyl)benzonitrile] had a reactivation efficacy comparable to the standard oxime HI-6. In silico analysis and molecular docking studies, including molecular dynamics simulation, connected kinetic data to the structural features of these oximes and confirmed their productive interactions with the active site of cyclosarin-inhibited BChE. Based on inhibition and reactivation and their ADMET properties regarding lipophilicity, CNS activity, and hepatotoxicity, these compounds could be considered for further development of CNS-active reactivators in OP poisoning as well as cholinesterase-targeted therapeutics in neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Full article
(This article belongs to the Special Issue The Role of Cholinesterases in Alzheimer’s Disease and Other Neurodegenerative Disorders)
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11 pages, 1959 KiB  
Article
Cholesterol Oxime Olesoxime Assessed as a Potential Ligand of Human Cholinesterases
by Dora Kolić, Goran Šinko, Ludovic Jean, Mourad Chioua, José Dias, José Marco-Contelles and Zrinka Kovarik
Biomolecules 2024, 14(5), 588; https://doi.org/10.3390/biom14050588 - 15 May 2024
Viewed by 570
Abstract
Olesoxime, a cholesterol derivative with an oxime group, possesses the ability to cross the blood–brain barrier, and has demonstrated excellent safety and tolerability properties in clinical research. These characteristics indicate it may serve as a centrally active ligand of acetylcholinesterase (AChE) and butyrylcholinesterase [...] Read more.
Olesoxime, a cholesterol derivative with an oxime group, possesses the ability to cross the blood–brain barrier, and has demonstrated excellent safety and tolerability properties in clinical research. These characteristics indicate it may serve as a centrally active ligand of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), whose disruption of activity with organophosphate compounds (OP) leads to uncontrolled excitation and potentially life-threatening symptoms. To evaluate olesoxime as a binding ligand and reactivator of human AChE and BChE, we conducted in vitro kinetic studies with the active metabolite of insecticide parathion, paraoxon, and the warfare nerve agents sarin, cyclosarin, tabun, and VX. Our results showed that both enzymes possessed a binding affinity for olesoxime in the mid-micromolar range, higher than the antidotes in use (i.e., 2-PAM, HI-6, etc.). While olesoxime showed a weak ability to reactivate AChE, cyclosarin-inhibited BChE was reactivated with an overall reactivation rate constant comparable to that of standard oxime HI-6. Moreover, in combination with the oxime 2-PAM, the reactivation maximum increased by 10–30% for cyclosarin- and sarin-inhibited BChE. Molecular modeling revealed productive interactions between olesoxime and BChE, highlighting olesoxime as a potentially BChE-targeted therapy. Moreover, it might be added to OP poisoning treatment to increase the efficacy of BChE reactivation, and its cholesterol scaffold could provide a basis for the development of novel oxime antidotes. Full article
(This article belongs to the Special Issue The Role of Cholinesterases in Alzheimer’s Disease and Other Neurodegenerative Disorders)
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