Modulating oxytocin activity and plasma stability by disulfide bond engineering

Muttenthaler, Markus, Andersson, Asa, Dantas de Araujo, Aline, Dekan, Zoltan, Lewis, Richard J. and Alewood, Paul F. (2010) Modulating oxytocin activity and plasma stability by disulfide bond engineering. Journal of Medicinal Chemistry, 53 24: 8585-8596. doi:10.1021/jm100989w

Author Muttenthaler, Markus
Andersson, Asa
Dantas de Araujo, Aline
Dekan, Zoltan
Lewis, Richard J.
Alewood, Paul F.
Title Modulating oxytocin activity and plasma stability by disulfide bond engineering
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0022-2623
Publication date 2010-12-23
Sub-type Article (original research)
DOI 10.1021/jm100989w
Volume 53
Issue 24
Start page 8585
End page 8596
Total pages 12
Place of publication Washington, DC, United States
Publisher American Chemical Society
Collection year 2011
Language eng
Formatted abstract
Disulfide bond engineering is an important approach to improve the metabolic half-life of cysteine-containing peptides. Eleven analogues of oxytocin were synthesized including disulfide bond replacements by thioether, selenylsulfide, diselenide, and ditelluride bridges, and their stabilities in human plasma and activity at the human oxytocin receptor were assessed. The cystathionine (Ki = 1.5 nM, and EC50 = 32 nM), selenylsulfide (Ki = 0.29/0.72 nM, and EC50 = 2.6/154 nM), diselenide (Ki = 11.8 nM, and EC50 = 18 nM), and ditelluride analogues (Ki = 7.6 nM, and EC50 = 27.3 nM) retained considerable affinity and functional potency as compared to oxytocin (Ki = 0.79 nM, and EC50 = 15 nM), while shortening the disulfide bridge abolished binding and functional activity. The mimetics showed a 1.5-3-fold enhancement of plasma stability as compared to oxytocin (t 1/2 = 12 h). By contrast, the all-d-oxytocin and head to tail cyclic oxytocin analogues, while significantly more stable with half-lives greater than 48 h, had little or no detectable binding or functional activity.
© 2010 American Chemical Society.
Keyword Phase peptide-synthesis
Amino-acid substitution
In-situ neutralization
Deamino analogs
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
Institute for Molecular Bioscience - Publications
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Created: Sun, 16 Jan 2011, 00:04:58 EST