A New Strategy To Stabilize Oxytocin in Aqueous Solutions: II. Suppression of Cysteine-Mediated Intermolecular Reactions by a Combination of Divalent Metal Ions and Citrate

Avanti, Christina; Permentier, Hjalmar P.; Dam, Annie van; Poole, Robert A.; Jiskoot, Wim; Frijlink, Henderik W.; Hinrichs, Wouter L. J.

doi:10.1021/mp200622z

Cited by 29 publications

(36 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The stability of OT in most common infusion solutions has been extensively studied, and in recent papers a stabilizing effect of divalent metal ions in citric acid buffers was demonstrated . Surprisingly, neither the structural features favoring chemical degradation in solution, nor the degradation mechanism, nor the identity of the degradation products, have been described in the literature.…”

Section: Introductionmentioning

confidence: 99%

On the mechanism of degradation of oxytocin and its analogues in aqueous solution

Wiśniewski¹,

Finnman²,

Flipo³

et al. 2013

Biopolymers

View full text Add to dashboard Cite

Oxytocin (OT) is a cyclic nonapeptide containing one internal disulfide bond between its Cys(1) and Cys(6) residues. Although OT is one of the most commonly used peptidic drugs, the mechanism of its degradation in aqueous solution and the identity of its degradants have not been fully elucidated. To investigate the pathways and products of OT degradation in slightly acidic to neutral solutions, we prepared the peptides: OT, [D-Cys(1)]OT, a series of N-alkylated OT analogues, [[(13)C3,(15) N]Cys(1)]OT, and OT where each sulfur atom was systematically replaced by either methylene, (34)S, or Se. The peptides were incubated at 40°C and the degradation products studied by HPLC, LCMS, and (13)C-NMR. Our findings suggest that the degradation begins with β-elimination of the disulfide linkage to form a putative intermediate linear peptide containing an S-thiocysteine (a persulfide) in position 6 and a dehydroalanine in position 1. This intermediate persulfide appears to donate a sulfur atom to an intact OT molecule to form OT trisulfide and higher monomeric polysulfides, while the dehydroalanine residue is hydrolyzed with loss of the N-terminal amino group to yield a linear N-pyruvoylated octapeptide containing a reduced Cys(6). Based on the MS and (13)C-NMR data of the products from degradation of [[(13)C3,(15)N]Cys(1)]OT, we postulate that the ultimate degradation products of OT are dimers composed of two pyruvoylated octapeptides held together by one disulfide bridge between the two Cys(6) residues and by one more, non-reducible, linkage resulting from an aldol-type condensation between the two N-terminal pyruvoyl groups.

show abstract

Section: Introductionmentioning

confidence: 99%

On the mechanism of degradation of oxytocin and its analogues in aqueous solution

Wiśniewski¹,

Finnman²,

Flipo³

et al. 2013

Biopolymers

View full text Add to dashboard Cite

show abstract

“…A number of strategies for improving aqueous stability or precluding the need for aqueous solutions of oxytocin are being explored, including; the use of excipients in aqueous formulation, disulfide bond engineering and peptide‐polymer conjugation …”

Section: Applications Of Protein/peptide Polymer Conjugatesmentioning

confidence: 99%

Synthesis and Applications of Protein/Peptide-Polymer Conjugates

Wilson

2017

Macromol. Chem. Phys.

View full text Add to dashboard Cite

Recent advances in synthetic methodologies have brought us closer than ever to the precision conferred by nature. For example, the control possible in reversible deactivation radical polymerization enables us to design and synthesize macromolecules with unprecedented control over not only the polymer chain ends, but also the side chain functionality. Furthermore, this functionality can be exploited to afford chemical modification of peptides and proteins, with ever‐improving site‐specificity, yielding a range of well‐defined protein/peptide‐hybrid materials. Such materials benefit from the amalgamation of the properties of proteins/peptides with those of the synthetic (macro)molecules in question. Here, the latest developments in the synthesis of functional polymers and their use for preparation of well‐defined protein/peptide‐polymer conjugates will be discussed, with particular attention focused on modulating the stability, efficacy and/or administration of therapeutic peptides.

show abstract

“…Based on kinetic analysis, pH 4.5 was identified as the most stable solution condition (58). Further stabilization has been achieved with the addition of divalent metal ions such as calcium, magnesium, and zinc in combination with buffers such as citrate or aspartate (59)(60)(61). One hypothesis is that the interaction of oxytocin, the metal ion, and the acidic buffer may contribute to stabilization of the peptide conformation, thereby reducing the risk of degradation (59).…”

Section: Parenteral Peptide Developability Case Studiesmentioning

confidence: 99%

Physicochemical and Formulation Developability Assessment for Therapeutic Peptide Delivery—A Primer

Bak

Leung

Barrett

et al. 2014

AAPS J

View full text Add to dashboard Cite

Abstract. Peptides are an important class of endogenous ligands that regulate key biological cascades. As such, peptides represent a promising therapeutic class with the potential to alleviate many severe disease states. Despite their therapeutic potential, peptides frequently pose drug delivery challenges to scientists. This review introduces the physicochemical, biophysical, biopharmaceutical, and formulation developability aspects of peptides pertinent to the drug discovery-to-development interface. It introduces the relevance of these properties with respect to the delivery modalities available for peptide pharmaceuticals, with the parenteral route being the most prevalent route of administration. This review also presents characterization strategies for oral delivery of peptides with the aim of illuminating developability issues with the drug candidate. A brief overview of other routes of administration, including inhaled, transdermal, and intranasal routes, is provided as these routes are generally preferred by patients over injectables. Finally, this review presents formulation techniques to mitigate some of the developability obstacles associated with peptide delivery. The authors emphasize opportunities for the thoughtful application of pharmaceutical science to the development of peptide drugs and to the general advancement of this promising class of pharmaceuticals.

show abstract

A New Strategy To Stabilize Oxytocin in Aqueous Solutions: II. Suppression of Cysteine-Mediated Intermolecular Reactions by a Combination of Divalent Metal Ions and Citrate

Cited by 29 publications

References 22 publications

On the mechanism of degradation of oxytocin and its analogues in aqueous solution

On the mechanism of degradation of oxytocin and its analogues in aqueous solution

Synthesis and Applications of Protein/Peptide-Polymer Conjugates

Physicochemical and Formulation Developability Assessment for Therapeutic Peptide Delivery—A Primer

Contact Info

Product

Resources

About