Discovery of Hyperstable Noncanonical Plant-Derived Epidermal Growth Factor Receptor Agonist and Analogs
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2021 |
|---|---|
| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:64 |
|---|---|
| Enthalten in: |
Journal of medicinal chemistry - 64(2021), 11 vom: 10. Juni, Seite 7746-7759 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Loo, Shining [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
EC 2.7.10.1 |
|---|
| Anmerkungen: |
Date Completed 17.06.2021 Date Revised 17.06.2021 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1021/acs.jmedchem.1c00551 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM325653291 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM325653291 | ||
| 003 | DE-627 | ||
| 005 | 20231225192908.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2021 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1021/acs.jmedchem.1c00551 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1085.xml |
| 035 | |a (DE-627)NLM325653291 | ||
| 035 | |a (NLM)34015925 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Loo, Shining |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Discovery of Hyperstable Noncanonical Plant-Derived Epidermal Growth Factor Receptor Agonist and Analogs |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 17.06.2021 | ||
| 500 | |a Date Revised 17.06.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Peptides |2 NLM | |
| 650 | 7 | |a Plant Proteins |2 NLM | |
| 650 | 7 | |a ErbB Receptors |2 NLM | |
| 650 | 7 | |a EC 2.7.10.1 |2 NLM | |
| 700 | 1 | |a Kam, Antony |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Bin Bin |e verfasserin |4 aut | |
| 700 | 1 | |a Feng, Nan |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xiaoliang |e verfasserin |4 aut | |
| 700 | 1 | |a Tam, James P |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of medicinal chemistry |d 1963 |g 64(2021), 11 vom: 10. Juni, Seite 7746-7759 |w (DE-627)NLM000006602 |x 1520-4804 |7 nnns |
| 773 | 1 | 8 | |g volume:64 |g year:2021 |g number:11 |g day:10 |g month:06 |g pages:7746-7759 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1021/acs.jmedchem.1c00551 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 64 |j 2021 |e 11 |b 10 |c 06 |h 7746-7759 | ||