P-310 - A peptide derived from naturally occurring surfactant protein A (SP-A) inhibits the phospholipase A2 (PLA2) activity of peroxiredoxin 6 (Prdx6) and NOX2 activation and prevents mouse lung injury following intratracheal LPS

Abstract

We have developed a peptide based on the naturally occurring 26 kDa SP-A protein that inhibits the PLA2 but not the GPx activity of Prdx6. A 16 aa sequence was predicted by the ZDOCK program as the molecular site for binding of SP-A to Prdx6 and was confirmed using ITC and CD measurements.The peptide (called PLA2-inhibitory peptide or PIP) inhibited the PLA2 activity of recombinant human Prdx6 by ~70% and similarly inhibited Prdx6-associated PLA2 activity in homogenates of mouse lungs while presence of the peptide prevented the activation of lung NOX2.We have found since that a 9 aa peptide, named PIP-2,retains the Prdx6-inhibitory properties of both the protein and PIP. PIP was tested in a mouse model of acute lung injury (ALI) generated by the intratracheal instillation of bacterial lipopolysaccharide (LPS).PIP was encapsulated in liposomes for intracellular delivery and administered IV to mice either co-incidentally with or at 12–14 h after LPS. Mouse lungs evaluated at 24 h after LPS showed a marked decrease of lung leukocytic infiltration, of altered permeability, and of the oxidation of tissue macromolecules in the animals receiving PIP. These studies suggest that PIP might be a useful therapeutic for the prevention and treatment of ALI.