Provided are novel, non-naturally occurring chagasin scaffold proteins derived from chagasin or chagasin-like protease inhibitor proteins. Also provided are libraries of non-naturally occurring chagasin scaffold proteins and methods of using such libraries to generate non-naturally occurring chagasin scaffold proteins that specifically bind to a target ligand. The present invention further provides methods of using non-naturally occurring chagasin protein scaffold that bind to a target ligand, including diagnostic and therapeutic compositions and methods. The invention also provides novel non-naturally occurring chagasin scaffold proteins that specifically bind low density lipoprotein receptor-related protein 6 (LRP6) and novel non-naturally occurring chagasin scaffold proteins that specifically bind vascular endothelial growth factor (VEGF).
