The interaction between oxytocin and heparin

Abstract

Oxytocin (OXT) is a small cyclic peptide that is administered to pregnant women to induce birth in cases where labour is prolonged. It has previously been observed that patients taking a low molecular weight heparin, dalteparin (DAL), and then prescribed, OXT experienced a swifter labour compared to women given OXT alone. Herein are described the interactions between OXT and a number of heparin-based oligosaccharides; DAL; fondaparinux (FP), which is a synthetic heparin oligosaccharide that represents the predominant antithrombin binding-site, and a family of chemically-derived heparin hexasaccharides. The latter oligosaccharides were chosen as they represent sequences found within the polysaccharide dalteparin. Furthermore, the carbohydrate chemical space was investigated by comparing the interaction between OXT and four chemically derivatived heparin hexasaccharides; I_2S-A^6S_NS (DP6), I_2OH-A^6S_NS (DP6-2OH, de-2-O-sulfated hexasaccharide), I_2S-A^6OH_NS (DP6-6OH, de-6-O-sulfated hexasaccharide) and I_2S-A^6S_NAc (DP6-NAc, de-N-sulfated hexasaccharide). The interactions between the peptide and oligosaccharides were studied using a series of ¹³C–¹H and ¹⁵N–¹H HSQC NMR experiments, at a range of temperatures. This approach allowed the binding epitopes of the peptide and oligosaccharides to be identified, highlighting that 6-O- and N-sulfation substituent groups of heparin are important for the interaction between the peptide and carbohydrate. This is an important observation as de-N-sulfation is a traditional method for decreasing the anticoagulation properties of heparin. Furthermore, low temperature experiments of the OXT : FP complex indicate that hydrogen-bonding is very important for the interaction between the peptide and oligosaccharide.