Abstract
The EPICC peptides are a family of peptides that have been developed from the sequence of the capsid protein of human astrovirus type 1 and previously shown to inhibit the classical and lectin pathways of complement. The EPICC peptides have been further optimized to increase aqueous solubility and identify additional mechanisms of action. Our laboratory has developed the lead EPICC molecule, PA-dPEG24 (also known as RLS-0071), which is composed of a 15 amino acid peptide with a C-terminal monodisperse 24-mer PEGylated moiety. RLS-0071 has been demonstrated to possess other mechanisms of action in addition to complement blockade that include the inhibition of neutrophil-driven myeloperoxidase (MPO) activity, inhibition of neutrophil extracellular trap (NET) formation as well as intrinsic antioxidant activity mediated by vicinal cysteine residues contained within the peptide sequence. RLS-0071 has been tested in various ex vivo and in vivo systems and has shown promise for the treatment of both immune-mediated hematological diseases where alterations in the classical complement pathway plays an important pathogenic role as well as in models of tissue-based diseases such as acute lung injury and hypoxic ischemic encephalopathy driven by both complement and neutrophil-mediated pathways (i.e., MPO activity and NET formation). Next generation EPICC peptides containing a sarcosine residue substitution in various positions within the peptide sequence possess aqueous solubility in the absence of PEGylation and demonstrate enhanced complement and neutrophil inhibitory activity compared to RLS-0071. This review details the development of the EPICC peptides, elucidation of their dual-acting complement and neutrophil inhibitory activities and efficacy in ex vivo systems using human clinical specimens and in vivo efficacy in animal disease models.
Highlights
The innate immune system is the body’s first line of defense against microorganisms
Based on sequence alignment data, we identified a 60 amino acid region of the Human astrovirus serotype 1 (HAstV-1) capsid protein that had limited homology to human neutrophil peptide-1 (HNP-1) [25] which had previously been identified as an inhibitor of the classical and lectin complement pathways [26]
Since the hemolysis from the incompatible blood products was found to be inhibited through the addition of RLS-0071 in the complement hemolysis using human erythrocytes” (CHUHE) assay, the potential for RLS-0071 as a prophylactic or rescue treatment was examined in a rat model of acute hemolytic transfusion reactions (AHTR)-like intravascular hemolysis after transfusion of incompatible red blood cells (RBC) [58]
Summary
The innate immune system is the body’s first line of defense against microorganisms. It consists of both humoral and cellular mechanisms that are triggered immediately upon infection. Two of the primary components of innate immunity are phagocytic cells (neutrophils and macrophages) and blood proteins (the complement system). While complement and neutrophils are an essential host defense against invasive microbes, dysregulation of the innate immune response plays a prominent role in a variety of inflammatory and autoimmune diseases. The discovery, in vitro and ex vivo characterization as well as the in vivo activity of these peptides in pre-clinical blood and tissue-based disease models, will be discussed along with their implications for therapeutic use in inflammatory disease processes
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
