UC Riverside

The Design and Evaluation of Peptoid Heparin Inhibitors

By

Bruce K. Ford

Doctor of Philosophy, Graduate Program in Chemistry

University of California, Riverside, August 2011

Dr. Dallas Rabinstein, Chairperson

Heparin has found use as an anticoagulant in medicine for more than 70 years1 and also plays important biological roles in addition to its involvement in the inhibition of the coagulant cascade. Since human blood has a tendency to clot in direct contact with plastics, intravenous lines are coated with heparin to inhibit coagulation during surgery, or in kidney dialysis and in other medical situations where blood is circulated extracorporeally, where it comes into direct contact with synthetic materials. Also heparan sulfate is added to the intravenous blood supply for the same purpose. Following a medical procedure of this type, it is nessary to reverse the effects of the heparin and heparan sulfate. Currently is the only substances available for this purpose. Protamine is derived from natural sources and possesses imunogenic effects.

In this study, a series of peptoids, which are analogs of peptides, have been designed, synthesized2 and studied with the goal of producing molecules with high binding affinity to heparin. The peptoids were produced through a solid phase synthesis methodology using a two step submonomer procedure to create each peptoid monomer unit, which were then joined together to produce a library of 18 peptoid analogs. These peptoids were designed and synthesized with amine bearing side chains strategically located along the peptoid sequence , resulting in cationic peptoids at neutral pH. The amine side chains were also converted to guanidium groups post synthesis of the peptoid oligomers to yield a second family of cationic peptoids that are analogs of arginine containing peptides. Upon synthesis of these two related libraries of peptoids, they were studied using a variety of methods including Isothermal Titration Calormemitry, Heparin Affinity Chromatography, TOF-Maldi MS, and Circular Dichroism.

The results of these studies indicated that it is possible to synthesize high-binding affinity peptoids to heparin. It is hoped that these peptoids, by binding tightly with heparin could potentially replace the too often immunogenic side effects of protamine currently in use in medicine today.

References

1. Folkman, J., Langer, R., Linhardt, R. J., Haudenschild, C.,Taylor, S. Science 1983, 221, 719-725.

2. Zuckermann, R. N., Kerr, J.M., Kent, S.B, Moos, W.H. J. Am. Chem. Soc. 1992, 114, 10646-10647.