# Selective Modulation of Trk Receptors by Cyclo-Organopeptides

## TL;DR

This paper explores new cyclo-organopeptides that activate Trk receptors, aiming to find better alternatives to neurotrophins for treating eye conditions like dry eye disease.

## Contribution

The study identifies new cyclo-organopeptides with improved Trk activation properties compared to existing compounds like D3.

## Key findings

- A new cyclo-organopeptide designed to mimic NT-3 showed superior relief of desiccating stress in mice.
- Three new compounds were tested alongside D3, revealing better in vivo performance.
- Challenges in optimizing and screening Trk agonists are discussed.

## Abstract

Neurotrophins (NTs, including NGF, BDNF, NT-4, and NT-3)
are extracellular
cytokines which modulate the survival and growth of cells expressing
tropomyosin receptor kinases (Trks) A–C. Cells which express
Trks include many neural tissues. For instance, corneal nerves secrete
NTs to counteract epithelium disruption. Potential therapeutic applications
of Trk agonism are numerous, but the use of NTs is limited by problems
with production, in vivo stability, and side effects of the protein.
Only humanized recombinant NGF has been clinically approved: Cenegermin
for treatment of neurotrophic keratitis (NK) in the eye. Consequently,
low molecular mass Trk agonists are of interest as surrogates for
humanized NTs. One low molecular mass TrkA modulator from our lab,
a cyclo-organopeptide D3, emerged as
a clinical candidate for treatment of dry eye disease and reached
phase 3 trials. However, it remains to be determined whether similar
agonists or modulators of other Trks might exhibit similar effects.
Moreover, D3 was moved into trials without much optimization.
This work was undertaken to identify cyclo-organopeptides
which would activate TrkA, B, and/or C and to compare their potencies
to D3. The immediate goal was to select compounds for
studies to probe relief from desiccating stress to the eye in a mouse
model relative to D3. In fact, in vivo assays on select
compounds developed in the work described here have already been published.
Three new cyclo-organopeptides selected for Trk agonism
or modulation and D3 were tested, and a superior lead
for relief of desiccating stress in vivo was identified. Interestingly,
that lead compound was designed to mimic NT-3, not NGF. This paper
describes how those new cyclo-organopeptides were
designed, prepared, and then selected via screens on Trk-transfected
cells. It also outlines and explains obstacles which limit progress
in this type of study.