De Novo Design of Integrin α5β1 Modulating Proteins for Regenerative Medicine

Abstract

Integrin 5{beta}1 is crucial for cell attachment and migration in development and tissue regeneration, and 5{beta}1 binding proteins could have considerable utility in regenerative medicine and next-generation therapeutics. We use computational protein design to create de novo 5{beta}1-specific modulating miniprotein binders, called NeoNectins, that bind to and stabilize the open state of 5{beta}1. When immobilized onto titanium surfaces and throughout 3D hydrogels, the NeoNectins outperform native fibronectin and RGD peptide in enhancing cell attachment and spreading, and NeoNectin-grafted titanium implants outperformed fibronectin and RGD-grafted implants in animal models in promoting tissue integration and bone growth. NeoNectins should be broadly applicable for tissue engineering and biomedicine. One-Sentence SummaryA de novo-designed fibronectin substitute, NeoNectin, is specific for integrin 5{beta}1 and can be incorporated into biomaterials for regenerative medicine.