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High-Throughput Screening for Positive Allosteric Modulators Identified Potential Therapeutics against

Richard R Chapleau1, Craig A McElroy2, Christopher D Ruark3

  • 1Henry M. Jackson Foundation for the Advancement of Military Medicine, Wright Patterson AFB, OH, USA Molecular Bioeffects Branch, Bioeffects Division, Human Effectiveness Directorate, 711th Human Performance Wing, Air Force Research Laboratory (711 HPW/RHDJ), Wright Patterson AFB, OH, USA richard.chapleau.1@us.af.mil.

Journal of Biomolecular Screening
|June 17, 2015
PubMed
Summary

Researchers identified novel compounds that enhance acetylcholinesterase (AChE) activity. These positive allosteric modulators (PAMs) offer potential new treatments for organophosphate poisoning, aiming to reduce side effects associated with current therapies.

Keywords:
acetylcholinesterasemedical countermeasurenerve agent pretreatmentorganophosphate poisoningpositive allosteric modulator

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Area of Science:

  • Biochemistry
  • Pharmacology
  • Toxicology

Background:

  • Organophosphate (OP) poisoning treatment relies on pyridostigmine bromide, an acetylcholinesterase (AChE) inhibitor with side effects.
  • There is a need for therapeutics that mitigate AChE inhibition without causing similar adverse effects.

Purpose of the Study:

  • To identify novel compounds that increase AChE catalytic activity.
  • To develop potential therapeutics for OP poisoning with improved safety profiles.

Main Methods:

  • High-throughput screening was employed to find compounds that enhance AChE activity.
  • The identified compounds were characterized for their effects on AChE activity and OP inhibition.

Main Results:

  • Two novel positive allosteric modulators (PAMs) of AChE were identified.
  • These PAMs increased AChE activity threefold but did not alter the IC50 for various OPs.

Conclusions:

  • The identified PAMs show promise for developing new pre- and/or postexposure therapeutics against OP poisoning.
  • Further optimization could lead to broad-spectrum efficacy and improved therapeutic options, potentially complementing existing treatments.