Structural Studies of a Peptide with Immune Modulating and Direct Antimicrobial Activity

Abstract

The structure and function of the synthetic innate defense regulator peptide 1018 was investigated. This 12 residue synthetic peptide derived by substantial modification of the bovine cathelicidin bactenecin has enhanced innate immune regulatory and moderate direct antibacterial activities. The solution state NMR structure of 1018 in zwitterionic dodecyl phosphocholine (DPC) micelles indicated an α-helical conformation, while secondary structures, based on circular dichroism measurements, in anionic sodium dodecyl sulfate (SDS) and phospholipid vesicles (POPC/PG in a 1:1 molar ratio) and simulations revealed that 1018 can adopt a variety of folds, tailored to its different functions. The structural data are discussed in light of the ability of 1018 to potently induce chemokine responses, suppress the LPS-induced TNF-α response, and directly kill both Gram-positive and Gram-negative bacteria.

Immunomodulatory Peptide IDR-1018 Decreases Implant Infection and Preserves Osseointegration

“…IDR-1018 has been reported to potently kill S aureus in bacterial broth [42]. However, physiologic ion levels block bactericidal effects of many HDPs [6,19,43].…”

“…However, orthopaedic infections can be especially difficult to combat [18,24] and IDRs have not been tested in that setting. Moreover, the immunomodulatory effects of IDR-1018 have only been characterized in response to lipopolysacharide [32,42], which is exclusively produced by Gram-negative bacteria.…”

“…As a result of their unique immunomodulatory mechanisms of action, HDPs are also less likely to induce bacterial resistance than are conventional antibiotics [14,15]. Innate defense regulator peptide-1018 (IDR-1018) is a synthetic 12-amino acid derivative of bactenecin, a bovine HDP [42]. IDR-1018 can directly kill bacteria [42], can modulate differentiation and activation of macrophages and neutrophils, thereby regulating their production of chemokines and cytokines [1,26,30,32,37,42], can reduce soft tissue infections [1,37], and can disrupt bacterial biofilms [25,35].…”

“…Innate defense regulator peptide-1018 (IDR-1018) is a synthetic 12-amino acid derivative of bactenecin, a bovine HDP [42]. IDR-1018 can directly kill bacteria [42], can modulate differentiation and activation of macrophages and neutrophils, thereby regulating their production of chemokines and cytokines [1,26,30,32,37,42], can reduce soft tissue infections [1,37], and can disrupt bacterial biofilms [25,35]. IDR-1018 was chosen as the focus of this study because it is the most potent IDR that has been described [37] and is therefore an attractive agent to potentially reduce orthopaedic infections and inflammatory osteolysis around orthopaedic implants.…”

Immunomodulatory activities of whey β-lactoglobulin tryptic-digested fractions

“…Although activation usually arises after exposure to pathogens or tissue injury, several short peptides, like natural host defence peptides (HDPs), can also stimulate macrophage differentiation. Therefore, in recent years there has been an increased effort to design and develop synthetic peptides, termed innate defence regulators (IDRs), with enhanced immunomodulatory activities that depend on uptake into eukaryotic cells, making them an attractive new anti-infective strategy for their potential value in the therapy and prophylaxis of infection (Nijnik et al, 2010;Wieczorek et al, 2010). Therefore, specific whey-derived peptides could act as natural IDRs.…”