TY - JOUR
T1 - Discovery of Hyperstable Noncanonical Plant-Derived Epidermal Growth Factor Receptor Agonist and Analogs
AU - Loo, Shining
AU - Kam, Antony
AU - Li, Bin Bin
AU - Feng, Nan
AU - Wang, Xiaoliang
AU - Tam, James P.
N1 - Funding Information:
This research was supported in part by the Competitive Research Grant by National Research Foundation in Singapore (NRF-CRP8–2011-05), Nanyang Technological University Internal Funding–Synzyme and Natural Products (SYNC), and the AcRF Tier 3 funding (MOE2016-T3–1-003). A.K. is a recipient of the Mistletoe Research Fellowship.
Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society.
PY - 2021/6/10
Y1 - 2021/6/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85108020821&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.1c00551
DO - 10.1021/acs.jmedchem.1c00551
M3 - Article
C2 - 34015925
AN - SCOPUS:85108020821
SN - 0022-2623
VL - 64
SP - 7746
EP - 7759
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 11
M1 - 64
ER -
