Islet Amyloid Polypeptide (IAPP, also known as Amylin) is a 37-residue, neuropancreatic hormone that is co-secreted with insulin by islet b-cells and plays an important role in glycemic control. The peptide is linked to diabetes mellitus, forming extracellular amyloid deposits in type 2 disease and largely absent in type 1 disease. IAPP is found in all vertebrates and the sequence is well conserved, but some variants exhibit decreased <i>in vitro</i> amyloidogenicity and enhanced solubility in formulation. Rat IAPP, a highly studied sequence, has previously been used in the development of an FDA-approved amylin analog pramlintide (Symlin), used in hormone replacement therapy. Low solubility at physiological pH, however, limits its ability to be co-formulated with insulin, limiting its use. We have identified common sequence motifs in interspecies variants that are often non-amyloidogenic. The present work includes the characterization of a novel variant, sheep IAPP, and incorporation of key moieties found in sheep, bovine, and other sequences in the design and characterization of novel analogs. These analogs are non-amyloidogenic, activate human amylin receptors, non-toxic, exhibit enhanced solubility, and represent a promising adjunct to insulin therapy in the treatment of diabetes mellitus.

From barnyard to bedside: Using interspecies variants to inform the rational design of novel analogs of islet amyloid polypeptide

ACS Spring 2022

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