Fragments of Nle³‐angiotensin(1–7) accelerate healing in dermal models

The renin angiotensin system (RAS) has been shown to be present in dermal tissue and exogenous peptides from the RAS accelerates healing and reduces scarring. An analogue of Angiotensin(1–7) [A(1–7)], Norleucine 3 ‐A(1–7) [Nle 3 ‐A(1–7)], is the lead compound under development for treatment of dermal injuries. As proteases are prevalent in wounded tissue and at very high levels in chronic wounds, the ability of fragments of Nle 3 ‐A(1–7) to accelerate healing and the effect of proteases on the peptide were determined. Daily application of fragments of Nle 3 ‐A(1–7) of five or six amino acids accelerated healing in two models of dermal injury. In addition, the peptide was found to be stable (not substantially degraded) after incubation for 4 h in the presence of Cathepsin G, collagenases blend (from clostridium), matrix metalloprotease [MMP] 2, MMP 3, MMP 9, elastase (human leukocytic or porcine pancreatic) or plasmin. Only kallikrein, an enzyme known to cleave peptides of the RAS, cleaved the peptide into two major fragments one of which was identified as NorLeu 3 ‐A(1–4). These data support the activity of Nle 3 ‐A(1–7) on dermal wounds.