posted on 2021-05-21, 07:04authored byShining 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.