Single-molecule imaging of small aggregates of IAPP in type 2 diabetes serum with rationally-designed antibody-like scaffolds

Abstract

The aggregation of the islet amyloid polypeptide (IAPP) plays an important role in the pathology of type 2 diabetes (T2D). However, the transient and heterogeneous nature of the aggregated forms of IAPP makes it challenging to study their behaviour. In this study, we employed an antibody scanning approach by designing a panel of nine peptides targeting subsequent epitopes along the IAPP sequence. These peptides were then grafted into engineered single-domain antibody and monobody scaffolds, resulting in two panels of antibody-like constructs. We first tested these constructs for their ability to inhibit IAPP aggregation and assessed their binding affinity towards different IAPP species. Then, we utilized these constructs to detect IAPP species in serum samples obtained from T2D patients. This study illustrates the opportunities offered by the computational epitope scanning method to develop antibody-like constructs for the detection of IAPP aggregates in biological samples.