Recruitment of αβ integrin to αβ integrin-induced clusters enables focal adhesion maturation and cell spreading.

The major fibronectin (FN)-binding αβ and αβ integrins exhibit cooperativity during cell adhesion, migration and mechanosensing, through mechanisms that are not yet fully resolved. Exploiting mechanically tunable nano-patterned substrates, and peptidomimetic ligands designed to selectively bind corresponding integrins, we report that focal adhesions (FAs) of endothelial cells assembled on αβ integrin-selective substrates rapidly recruit αβ integrins, but not vice versa. Blocking of αβ integrin hindered FA maturation and cell spreading on αβ integrin-selective substrates, indicating a mechanism dependent on extracellular ligand binding and highlighting the requirement of αβ integrin engagement for efficient adhesion.

Control of stem cell response and bone growth on biomaterials by fully non-peptidic integrin selective ligands.

In this communication we report that anchoring αvβ3 or α5β1 integrin-selective RGD peptidomimetics to titanium efficiently tunes mesenchymal stem cell response in vitro and bone growth in rat calvarial defects. Our results demonstrate that this molecular chemistry-derived approach could be successful to engineer instructive coatings for orthopedic applications.

Overcoming the Lack of Oral Availability of Cyclic Hexapeptides: Design of a Selective and Orally Available Ligand for the Integrin αvβ3.

A highly systematic approach for the development of both orally bioavailable and bioactive cyclic N-methylated hexapeptides as high affinity ligands for the integrin αvβ3 is based on two concepts: a) screening of systematically designed libraries with spatial diversity and b) masking of the peptide charge with a lipophilic protecting group. The key steps of the method are 1) initial design of a combinatorial library of N-methylated analogues of the stem peptide cyclo(d-Ala-Ala ); 2) selection of cyclic peptides with the highest intestinal permeability; 3) design of sublibraries with the bioactive RGD sequence in all possible positions; 4) selection of the best ligands for RGD-recognizing integrin subtypes; 5) fine-tuning of the affinity and selectivity by additional Ala to Xaa substitutions; 6) protection of the charged functional groups according to the prodrug concept to regain intestinal and oral permeability; 7) proof of biological effects in mice after oral administration.