A fluorescent electrophile for CLIPS: self indicating TrkB binders.
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abstract
Combination of cysteine-containing peptides with electrophiles provides efficient access to cyclo-organopeptides. However, there are no routes to intrinsically fluorescent cyclo-organopeptides containing robust, brilliant fluorophores emitting at wavelengths longer than cellular autofluorescence. We show such fluorescent cyclo-organopeptides can be made via SNAr reactions of cysteine-containing peptides with a BODIPY system. Seven compounds of this type were prepared to test as probes; six contained peptide sequences corresponding to loop regions in brain-derived neurotrophic factor and neurotrophic factor 4 (BDNF and NT-4) which bind tropomyocin receptor kinase B (TrkB). Cellular assays in serum-free media indicated two of the six key compounds induced survival of HEK293 cells stably transfected with TrkB whereas a control did not. The two compounds inducing cell survival bound TrkB on those cells (Kd 40 and 47 nM), illustrating how intrinsically fluorescent cyclo-organopeptides can be assayed for quantifiable binding to surface receptors in cell membrane environments.
