Here we report the use of sulfur-oxygen interactions as a conformational control element in a new class of peptidomimetic scaffolds. Solution and solid-state conformational analysis indicates that the scaffolds mimic key elements of alpha-helical secondary structure. The molecules disrupt the fibrillation of islet amyloid polypeptide (IAPP), a process that is implicated in the pathology of type II diabetes, most likely operating via an alpha-helix-dependent mechanism.