Transglutaminase-catalyzed covalent anti-myostatin peptide depots

Eur J Pharm Biopharm. 2024 Oct:203:114462. doi: 10.1016/j.ejpb.2024.114462. Epub 2024 Aug 26.

Abstract

Nature realizes protein and peptide depots by catalyzing covalent bonds with the extracellular matrix (ECM) of tissues. We are translating this natural blueprint for the sustained delivery of a myostatin-inhibiting peptide (Anti-Myo), resulting in an enzyme depot established from injectable solutions. For that, we fused Anti-Myo to the D-domain of insulin-like growth factor I, a transglutaminase (TG) substrate. TG catalyzed the covalent binding of the D-domain to ECM proteins, such as laminin and fibronectin, on bioengineered ECM and in mice. ECM decorated with Anti-Myo suppressed myostatin activity and pathway activation and reduced the differentiation of preconditioned bone marrow-derived macrophages into osteoclasts in vitro.

Keywords: Drug depot; Extracellular matrix; Myostatin inhibition; Solid phase peptide synthesis; Transglutaminase.

MeSH terms

  • Animals
  • Cell Differentiation / drug effects
  • Delayed-Action Preparations
  • Extracellular Matrix / metabolism
  • Humans
  • Insulin-Like Growth Factor I / administration & dosage
  • Insulin-Like Growth Factor I / metabolism
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Myostatin* / metabolism
  • Peptides / chemistry
  • Transglutaminases* / metabolism

Substances

  • Transglutaminases
  • Myostatin
  • Peptides
  • Insulin-Like Growth Factor I
  • Delayed-Action Preparations