Modulating Oxytocin Activity and Plasma Stability by Disulfide Bond Engineering

• Published in: Journal of medicinal chemistry Vol. 53; no. 24; pp. 8585 - 8596
• Main Authors: Muttenthaler, Markus, Andersson, Asa, de Araujo, Aline D, Dekan, Zoltan, Lewis, Richard J, Alewood, Paul F
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 23-12-2010
• Subjects: Alkylation; Disulfides - chemistry; Drug Stability; Half-Life; Humans; Organometallic Compounds - blood; Organometallic Compounds - chemical synthesis; Organoselenium Compounds - blood; Organoselenium Compounds - chemical synthesis; Oxidation-Reduction; Oxytocin - analogs & derivatives; Oxytocin - blood; Oxytocin - chemical synthesis; Peptidomimetics - blood; Peptidomimetics - chemical synthesis; Radioligand Assay; Receptors, Oxytocin - metabolism; Stereoisomerism; Structure-Activity Relationship; Sulfides - blood; Sulfides - chemical synthesis; Tellurium
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm100989w

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 (K i = 1.5 nM, and EC50 = 32 nM), selenylsulfide (K i = 0.29/0.72 nM, and EC50 = 2.6/154 nM), diselenide (K i = 11.8 nM, and EC50 = 18 nM), and ditelluride analogues (K i = 7.6 nM, and EC50 = 27.3 nM) retained considerable affinity and functional potency as compared to oxytocin (K i = 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.