This preprint is under consideration at Scientific Reports. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research Article
Carlos A. Valdez
Lawrence Livermore National Laboratory
Corresponding Author
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Nerve agents have experienced a resurgence in recent times with their use against civilian targets during the attacks in Syria (2012), the poisoning of Sergei and Yulia Skripal in the United Kingdom (2018) and Alexei Navalny in Russia (2020), strongly renewing the importance of antidote development against these lethal substances. The current standard treatment against their effects relies on the use of small molecule-based oximes that can efficiently restore acetylcholinesterase (AChE) activity. Despite their efficacy in reactivating AChE, the action of drugs like 2-pralidoxime (2-PAM) is primarily limited to the peripheral nervous system (PNS) and, thus, provides no significant protection to the central nervous system (CNS). This lack of action in the CNS stems from their ionic nature that, on one end makes them very powerful reactivators and on the other renders them ineffective at crossing the Blood Brain Barrier (BBB) to reach the CNS. In this report, we describe the use of an iterative approach composed of parallel chemical and in silico syntheses, computational modeling, and a battery of detailed in vitro and in vivo assays that resulted in the identification of a promising, novel CNS-permeable oxime reactivator. Additional experiments to determine acute and chronic toxicity are ongoing.
Keywords
Acetylcholineasterase (AChE), computer modeling, permeability, central nervous system (CNS), drug discovery, drug design
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
No competing interests reported.
This is a list of supplementary files associated with this preprint. Click to download.
Loading...
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 17 Mar, 2021
No community comments so far
Review #2 received
Received 04 Apr, 2021
Review #1 received
Received 04 Apr, 2021
Reviewer #3 agreed
On 24 Mar, 2021
Reviewer #6 agreed
On 24 Mar, 2021
Reviewer #1 agreed
On 24 Mar, 2021
Reviewer #2 agreed
On 24 Mar, 2021
Reviewer #5 agreed
On 24 Mar, 2021
Reviewer #4 agreed
On 24 Mar, 2021
Reviewers invited
Invitations sent on 24 Mar, 2021
Editor assigned
On 12 Mar, 2021
Editor invited
On 12 Mar, 2021
Submission checks complete
On 12 Mar, 2021
First submitted
On 05 Mar, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Learn more about our company.
This preprint is under consideration at Scientific Reports. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research Article
Carlos A. Valdez
Lawrence Livermore National Laboratory
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 17 Mar, 2021
No community comments so far
Review #2 received
Received 04 Apr, 2021
Review #1 received
Received 04 Apr, 2021
Reviewer #3 agreed
On 24 Mar, 2021
Reviewer #6 agreed
On 24 Mar, 2021
Reviewer #1 agreed
On 24 Mar, 2021
Reviewer #2 agreed
On 24 Mar, 2021
Reviewer #5 agreed
On 24 Mar, 2021
Reviewer #4 agreed
On 24 Mar, 2021
Reviewers invited
Invitations sent on 24 Mar, 2021
Editor assigned
On 12 Mar, 2021
Editor invited
On 12 Mar, 2021
Submission checks complete
On 12 Mar, 2021
First submitted
On 05 Mar, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Nerve agents have experienced a resurgence in recent times with their use against civilian targets during the attacks in Syria (2012), the poisoning of Sergei and Yulia Skripal in the United Kingdom (2018) and Alexei Navalny in Russia (2020), strongly renewing the importance of antidote development against these lethal substances. The current standard treatment against their effects relies on the use of small molecule-based oximes that can efficiently restore acetylcholinesterase (AChE) activity. Despite their efficacy in reactivating AChE, the action of drugs like 2-pralidoxime (2-PAM) is primarily limited to the peripheral nervous system (PNS) and, thus, provides no significant protection to the central nervous system (CNS). This lack of action in the CNS stems from their ionic nature that, on one end makes them very powerful reactivators and on the other renders them ineffective at crossing the Blood Brain Barrier (BBB) to reach the CNS. In this report, we describe the use of an iterative approach composed of parallel chemical and in silico syntheses, computational modeling, and a battery of detailed in vitro and in vivo assays that resulted in the identification of a promising, novel CNS-permeable oxime reactivator. Additional experiments to determine acute and chronic toxicity are ongoing.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Loading...