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Structure‐activity analysis of histatin, a potent wound healing peptide from human saliva: cyclization of histatin potentiates molar activity 1000‐fold
Author(s) -
Oudhoff Menno J.,
Kroeze Kim L.,
Nazmi Kamran,
Keijbus Petra A. M.,
Hof Wim,
Fernandez-Borja Mar,
Hordijk Peter L.,
Gibbs Susan,
Bolscher Jan G. M.,
Veerman Enno C. I.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.09-137588
Subject(s) - wound healing , peptide , saliva , chemistry , inflammation , receptor , microbiology and biotechnology , pharmacology , biochemistry , immunology , biology
ABSTRACT Wounds in the mouth heal faster and with less scarification and inflammation than those in the skin. Saliva is thought to be essential for the superior oral wound healing, but the involved mechanism is still unclear. We have previously discovered that a human‐specific peptide, histatin, might be implicated in the wound‐healing properties of saliva. Here we report that histatin enhances reepithelialization in a human full‐skin wound model closely resembling normal skin. The peptide does not stimulate proliferation but induces cell spreading and migration, two key initiating steps in reepithelialization. Activation of cells by histatin requires a G‐protein‐coupled receptor that activates the ERK1/2 pathway. Using a stepwise‐truncation method, we determined the minimal domain (SHREFPFYGDYGS) of the 38‐mer‐parent peptide that is required for activity. Strikingly, N‐ to C‐terminal cyclization of histatin‐1 potentiates the molar activity ̃1000‐fold, indicating that the recognition of histatin by its cognate receptor requires a specific spatial conformation of the peptide. Our results emphasize the importance of histatin in human saliva for tissue protection and recovery and establish the experimental basis for the development of synthetic histatins as novel skin wound‐healing agents.—Oudhoff, M. J., Kroeze, K. L., Nazmi, K., van den Keijbus, P. A. M., van't Hof, W., Fernandez‐Borja, M., Hordijk, P. L., Gibbs, S., Bolscher, J. G. M., Veerman, E. C. I. Structure‐activity analysis of histatin, a potent wound healing peptide from human saliva: cyclization of histatin potentiates molar activity 1000‐fold. FASEB J. 23, 3928–3935 (2009). www.fasebj.org