Selective Modulation of Trk Receptors by Cyclo-Organopeptides

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.