| Summary: | Here, we report the discovery of the first plant-
derived and noncanonical epidermal growth factor receptor
(EGFR) agonist, the 36-residue bleogen pB1 from Pereskia bleo
of the Cactaceae family. We show that bleogen pB1 is a low-affinity
EGFR agonist using a suite of chemical, biochemical, cellular, and
animal experiments which include incisor eruption and wound-
healing mouse models. A focused positional scanning pB1 library
of Ala- and D-amino acid scans yielded a high-affinity pB1 analog,
[K29k]pB1, with a 60-fold-improved EGFR affinity and
mitogenicity. We show that the potency of [K29k]pB1 and the
epidermal growth factor (EGF) is comparable in a diabetic mouse
wound-healing model. We also show that both bleogen pB1 and
[K29k]pB1 are hyperstable, being >100-fold more stable than EGF
against proteolytic degradation. Overall, our discovery of a noncanonical proteolytic-resistant EGFR agonist scaffold could open new avenues for developing wound healing and skin regeneration therapeutics and biomaterials.
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