Discovery of Hyperstable Noncanonical Plant-Derived Epidermal Growth Factor Receptor Agonist and Analogs
journal contributionposted on 2021-05-21, 07:04 authored by Shining Loo, Antony Kam, Bin Bin Li, Nan Feng, Xiaoliang Wang, James P. Tam
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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K 29kHyperstable Noncanonical Plant-Deri...noncanonical proteolytic-resistant ...epidermal growth factorhigh-affinity pB 1 analogd-amino acid scans60- fold-improved EGFR affinitymouse wound-healing modelskin regeneration therapeuticsnoncanonical epidermal growth facto...36- residue bleogen pB 1wound-healing mouse modelsscanning pB 1 librarylow-affinity EGFR agonistbleogen pB 1