De Novo Design of Integrin α5β1 Modulating Proteins for Regenerative Medicine

Xinru Wang; Jordi Guillem‐Marti; Saurav Kumar; David S. Lee; Daniel Cabrerizo‐Aguado; Rachel A. Werther; Kevin Alexander Estrada Alamo; Yan Ting Zhao; Adam Nguyen; Irina Kopyeva; Buwei Huang; Jing Li; Yuxin Hao; Xinting Li; Aritza Brizuela‐Velasco; Analisa Murray; Stacey Gerben; Anindya Roy; Cole A. DeForest; Timothy A. Springer; Hannele Ruohola‐Baker; Jonathan A. Cooper; Melody G. Campbell; José María Manero; Maria‐Pau Ginebra; David A. Baker

doi:10.1002/adma.202500872

BioengineeringAdvanced MaterialsJun 9, 2025

Peer-reviewed journal article

De Novo Design of Integrin α5β1 Modulating Proteins for Regenerative Medicine

Xinru Wang iD, Jordi Guillem‐Marti iD, Saurav Kumar iD, David S. Lee iD, Daniel Cabrerizo‐Aguado iD, Rachel A. Werther iD, Kevin Alexander Estrada Alamo iD, Yan Ting Zhao iD, Adam Nguyen iD, Irina Kopyeva iD, Buwei Huang iD, Jing Li iD, Yuxin Hao iD, Xinting Li iD, Aritza Brizuela‐Velasco iD, Analisa Murray, Stacey Gerben iD, Anindya Roy iD, Cole A. DeForest iD, Timothy A. Springer iD, Hannele Ruohola‐Baker iD, Jonathan A. Cooper iD, Melody G. Campbell iD, José María Manero iD, Maria‐Pau Ginebra iD, David A. Baker iD

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.

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