Selective, Intrinsically Fluorescent Trk Modulating Probes

Abstract

Neurotrophins (NTs) elicit the growth, survival, and differentiation of neurons and other neuroectoderm tissues via activation of Trk receptors. Hot spots for NT•Trk interactions involve three neurotrophin loops. Mimicry of these using "cyclo-organopeptides" comprising loop sequences cyclized onto endocyclic organic fragments accounts for a few of the low molecular mass Trk agonists or modulators reported so far; the majority are nonpeptidic small molecules accessed without molecular design and identified in random screens. It has proven difficult to verify activities induced by low molecular mass substances are due to Trk activation (rather than via other receptors), enhanced Trk expression, enhanced NT expression, or other pathways. Consequently, identification of selective probes for the various Trk receptors (e.g., A, B, and C) has been very challenging. Further, a key feature of probes for early stage assays is that they should be easily detectable, and none of the compounds reported to date are. In this work, we designed novel cyclo-organopeptide derivatives where the organic fragment is a BODIPY fluor and found ones that selectively, though not specifically, activate TrkA, B, or C. One of the assays used to reach this conclusion (binding to live Trkexpressing cells) relied on intrinsic fluorescence in the tested materials. Consequently, this work established low molecular mass Trkselective probes exhibiting neuroprotective effects.