Sayak Banerjee, Amity University Kolkata
Nerve agents, also known as nerve gases, belong to a class of organic chemicals that interrupts the nerves from transferring messages to organs. This interruption takes place due to the blocking of acetylcholinesterase (AChE), an enzyme that catalyzes the breakdown of the neurotransmitter, acetylcholine. So basically nerve agents are AChE inhibitors used as a poison. These are man-made agents manufactured for their application in chemical warfare. The most toxic chemicals ever manufactured are the class of organophosphorus-based nerve agents (OPNAs). Their lethality and ease of production contribute to their toxicity. Other members of the class including soman, tabun, sarin, and VX, also possess a high potential for mass casualties.
Organophosphorus-based nerve agents (OPNAs) as a class of nerve agents that are considered to be the most toxic chemicals ever manufactured owing to their ease of production and lethality. The public eye has witnessed a re-emergence of nerve agents in recent trans-national conflicts and assassinations. The subjection to OPNAs too leads to rapid inactivation of the enzyme AChE in both central and peripheral nervous systems (CNS, PNS). As a result, a covalently adducted AChE is formed which can give rise to convulsions, respiratory distress, seizures, and eventually death.
Working of Therapeutics
Owing to the swift toxicity of OPNAs, an effective therapeutic with a rapid treatment outcome is needed to counter these consequences after exposure. To date, several antidotes have been made to reactivate the inhibited AChE to its functional form. 2-pralidoxime (2-PAM), an antidote developed 60 years ago and which was approved by the US FDA, is a quaternary pyridinium oxime. Nevertheless, 2-PAM’s positively charged nitrogen center restricts it from crossing the blood-brain barrier (BBB), substantially revoking the CNS potency. On the contrary, OPNAs being hydrophobic, actively cross the BBB, thus impair the CNS function. Hence, a neutral and more hydrophobic small molecule is required to be developed that will cross the blood-brain barrier and reactivate the inhibited AChE for both PNS and CNS efficiency.
Researchers from Lawrence Livermore National Laboratory and three other universities in the United States have employed an iterative approach to identify a promising reactivator candidate. This approach parallelly involves the efforts in chemical synthesis, computational docking, bioassays, and in vitro, and in vivo capabilities. A computational library of virtual compounds was created and the compounds were ranked as per synthetic tractability. All synthesized compounds were put through in vitro reactivation and permeability assay.
From the data generated, four key structural characteristics were observed in the oxime they characterized.
i. The alkyl ring size was large, exhibiting greater activity.
ii. An ionizable nitrogen atom distal to the amide nitrogen was entailed for considerable reactivation.
iii. permeability was increased on the adding benzo moiety on the azepine ring.
iv. An additional chiral methyl group was indulged between the distal and amide nitrogen atoms.
With the final structural-activity relationship, the scientists had succeeded in developing a compound with increased permeability and significant reactivation activity. Low reactivation and permeability were exhibited by secondary cyclic amines. A reasonably well execution was carried out by the benzoazepine class depicted by LLNL-02 in both permeability and reactivation.
Blood-Brain Barrier and other hurdles
Various factors are probable to affect the potential of a given compound to cross BBB. The blood-brain barrier is made up of tightly apposed microvascular endothelial cells that inhibit molecular traversal. Although Diffusion and active transport give access across this barrier, efflux pumps such as p-glycoprotein could further inhibit the permeability. To examine these, three metrics of permeability were incorporated to determine compound behavior at BBB. The PAMPA system was employed to detect membrane diffusion. Human cerebral microvascular endothelial cell (HCMEC) traversal was employed to assess active uptake and cell diffusion. MDR1-MDCK (Multidrug resistance protein 1-MDCK) assay was used to determine p-gp efflux substrate specificity.
Conclusion
The researchers have made an end-to-end pipeline for the screening of probable CNS-permeable reactivators. The efficacy in the development of potential therapeutics has increased with the use of this pipeline. They came to the conclusion of identifying a novel CNS-permeable oxime reactivator (LLNL-02). The promising compound had favorable results in both in vitro and in vivo tests. Further research is necessary for the assessment of in vivo efficacy and toxicity of LLNL-02 to decide whether future development is warranted.
Also read: Respiratory Cryptosporidiosis: affecting children with diarrheal disease
Reference: Bennion, Brian J., et al. “Development of a CNS-Permeable Reactivator for Nerve Agent Exposure: An Iterative, Multi-Disciplinary Approach.” Scientific Reports, vol. 11, no. 1, Dec. 2021, p. 15567. https://doi.org/10.1038/s41598-021-94963-2.
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About Author
Sayak Banerjee is a 3rd-year Biotechnology Engineering Student with a great interest in Immunology and Molecular genetics. He is a creative scientific writer in Bioxone with an inclination towards gaining knowledge regarding vast sections of Biotechnology and emphasizing himself in various wet lab skills.
Publications:
- https://bioxone.in/news/worldnews/car-t-cells-scientists-discover-on-off-switches-for-cell-immunotherapy/
- https://bioxone.in/news/worldnews/neutrophil-derived-nanovesicles-a-novel-drug-delivery-system/
- https://bioxone.in/news/worldnews/pig-to-human-heart-transplantation-a-solution-to-the-rarity-of-donor-organs/
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