Selective Modulation of Trk Receptors by Cyclo-Organopeptides.

Area of Science:

• Neuroscience
• Pharmacology
• Ophthalmology

Background:

• Neurotrophins (NTs) like NGF and BDNF regulate cell survival and growth via Tropomyosin Receptor Kinases (Trks).
• Current NT-based therapies face challenges in production, stability, and side effects, limiting their clinical use.
• Small molecule Trk agonists are sought as alternatives, with D3 (a cyclo-organopeptide) showing promise for dry eye disease.

Purpose of the Study:

• To identify novel cyclo-organopeptides that activate TrkA, TrkB, and/or TrkC.
• To compare the potency of these new compounds against the existing TrkA modulator, D3.
• To select promising candidates for further investigation in models of ocular surface disease.

Main Methods:

• Design and synthesis of novel cyclo-organopeptides targeting Trk receptors.
• In vitro screening of compounds for Trk agonism or modulation using Trk-transfected cells.
• In vivo evaluation of selected compounds for relief of desiccating stress in a mouse model.

Main Results:

• Three new cyclo-organopeptides were designed, synthesized, and screened for Trk activity.
• A superior lead compound, designed to mimic NT-3, was identified for relieving desiccating stress.
• The new lead compound demonstrated enhanced efficacy compared to D3 in vivo.

Conclusions:

• Novel cyclo-organopeptides can be designed to target Trk receptors for therapeutic benefit.
• A lead compound mimicking NT-3 shows significant potential for treating ocular surface conditions like dry eye.
• Further optimization and investigation are warranted to overcome challenges in developing Trk-targeting therapeutics.