Type-II diabetes, caused by chronic insulin resistance and a progressive decline in pancreatic b-cell function, affects over 150 million people worldwide [1]. The 37-mer Human islet amyloid polypeptide (IAPP) (Figure 1) or amylin, is a major contributor to the amyloid deposits found in the pancreases of patients with type-II diabetes [2,3]. Amylin is highly hydrophobic and prone to aggregation, making it a difficult peptide to synthesize in sufficient purity and yield [4]. To our knowledge, the application of heat during coupling reactions of amylin synthesis has not been fully assessed and may provide an advantage for reducing on resin aggregation. Automated on-resin disulfide bridge formation in amylin using Tl(tfa)3, a mild oxidant, can provide better yields and purities of the desired cyclic products, compared to other methods.
H-KCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTY-NH2
Figure 1. Amylin structure (disulfide bond between residues 2 and 7).
References:
[1] (a) G.J.S. Cooper, A.C. Willis, A. Clark, R.C. Turner, R.B. Sim, K.B.M. Reid. Proc. Natl. Acad. Sci. USA, 84, 8628-8632 (1987). (b) P. Westermark, C. Wernstedt, E. Wilander, D.W. Hayden, T.D. O’Brien, K.H. Johnson. Proc. Natl. Acad. Sci. USA, 84, 3881-3885, (1987). (c) P.C. Butler, J. Chou, W.B. Carter, Y.N. Wang, B.H. Bu, D. Chang, J.K. Chang, R.A.. Rizza, Diabetes, 39, 752-755 (1990).
[2] A. Abedini and D.P. Raleigh. Biochemistry, 44, 16284-16291 (2005).
[3] A. Clark, C.A. Wells, I.D. Buley, J.K. Cruickshank, R.I. Vanhegan, D.R. Matthews, G.J. Cooper, R.R. Holman, R.C. Turner. Diabetes Res., 9, 151 (1988).
[4] Karen Pillay and Patrick Govender, “Amylin Uncovered: A Review on the Polypeptide Responsible for Type II Diabetes,” BioMed Research International, vol. 2013