Modulating oxytocin activity and plasma stability by disulfide bond engineering.
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(½) = 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.
Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Brisbane, Queensland.
Markus
M
Muttenthaler
Asa
A
Andersson
Aline D
AD
de Araujo
Zoltan
Z
Dekan
Richard J
RJ
Lewis
Paul F
PF
Alewood
D000478:Alkylation; D004220:Disulfides / Q000737:chemistry*; D004355:Drug Stability; D006207:Half-Life; D006801:Humans; D009942:Organometallic Compounds / Q000097:blood / Q000138:chemical synthesis*; D016566:Organoselenium Compounds / Q000097:blood / Q000138:chemical synthesis; D010084:Oxidation-Reduction; D010121:Oxytocin / Q000031:analogs & derivatives* / Q000097:blood / Q000138:chemical synthesis*; D057786:Peptidomimetics / Q000097:blood / Q000138:chemical synthesis*; D011869:Radioligand Assay; D018045:Receptors, Oxytocin / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000097:blood / Q000138:chemical synthesis; D013691:Tellurium
D004220:Disulfides; D009942:Organometallic Compounds; D016566:Organoselenium Compounds; D057786:Peptidomimetics; D018045:Receptors, Oxytocin; D013440:Sulfides; D010121:Oxytocin; D013691:Tellurium