Bioinspired covalent peptide drug depots in extracellular matrixmediated by transglutaminase Factor XIIIa

Nature creates local protein depots by forming covalent bonds to the extracellular matrix (ECM) of tissues. We are translating this natural blueprint for the sustained delivery of therapeutic peptides, that otherwise would be eliminated from the body rapidly.

In this study, a myostatin-inhibiting peptide is functionalised with the D-domain of insulin-like growth factor I, a substrate of transglutaminases. Myostatin promotes osteoclast differentiation and bone degradation in joint diseases, therefore myostatin inhibitors have an interesting therapeutic potential against arthritis.

The transglutaminase Factor XIIIa (FXIIIa) catalysed the binding of the peptide to ECM proteins, such as laminin and fibronectin, as indicated by tandem mass spectrometry. The immobilised construct suppressed Myostatin activity and pathway activation, demonstrated in 2D and 3D cell culture experiments, and reduced the differentiation of bone marrow-derived macrophages into osteoclasts. This bioinspired platform technology holds the potential to leverage the use of local drug depots, as it substantially reduces the development and manufacturing complexity, stability issues and risks during application of localized drug depots.