Inhibition of Lipopolysaccharide- and Lipoprotein-Induced Inflammation by Antitoxin Peptide Pep19-2.5

Abstract

The most potent cell wall-derived inflammatory toxins (“pathogenicity factors”) of Gram-negative and -positive bacteria are lipopolysaccharides (LPS) (endotoxins) and lipoproteins (LP), respectively. Despite the fact that the former signals via toll-like receptor 4 (TLR4) and the latter via TLR2, the physico-chemistry of these compounds exhibits considerable similarity, an amphiphilic molecule with a polar and charged backbone and a lipid moiety. While the exterior portion of the LPS (i.e., the O-chain) represents the serologically relevant structure, the inner part, the lipid A, is responsible for one of the strongest inflammatory activities known. In the last years, we have demonstrated that antimicrobial peptides from the Pep19-2.5 family, which were designed to bind to LPS and LP, act as anti-inflammatory agents against sepsis and endotoxic shock caused by severe bacterial infections. We also showed that this anti-inflammatory activity requires specific interactions of the peptides with LPS and LP leading to exothermic reactions with saturation characteristics in calorimetry assays. Parallel to this, peptide-mediated neutralization of LPS and LP involves changes in various physical parameters, including both the gel to liquid crystalline phase transition of the acyl chains and the three-dimensional aggregate structures of the toxins. Furthermore, the effectivity of neutralization of pathogenicity factors by peptides was demonstrated in several in vivo models together with the finding that a peptide-based therapy sensitizes bacteria (also antimicrobial resistant) to antibiotics. Finally, a significant step in the understanding of the broad anti-inflammatory function of Pep19-2.5 was the demonstration that this compound is able to block the intracellular endotoxin signaling cascade.

A highly efficient hybrid peptide ameliorates intestinal inflammation and mucosal barrier damage by neutralizing lipopolysaccharides and antagonizing the lipopolysaccharide‐receptor interaction

“…[22][23][24] According to some studies, the anti-inflammatory activity of peptides is tightly associated with their capacity to neutralize LPS. 43,44,55 Cationic AMPs engage in strong electrostatic interactions with the negatively charged LPS, and their positive charge enables stable embedment in amphiphilic LPS micelles. 44,55,56 It has been demonstrated that a high positive charge can strengthen the ability of AMPs to bind, neutralize, and inactivate LPS.…”

“…The enhanced LPS-neutralizing activity of C-L may be mainly attributed to its higher net positive charge, consistent with previous studies. 43,44,55,56,103 A higher net positive charge, therefore, should be considered when designing anti-inflammatory peptides and hybridizing is a good approach for achieving this aim. In addition, the present results suggest that C-L has potential to serve as a therapeutic drug for neutralizing endotoxin, substituting the traditional agent PMB, a well-known cyclic hydrophobic F I G U R E 1 1 C-L treatment do not alter the lipid rafts on the RAW264.7 macrophages membrane.…”

“…37,38 In addition to their antimicrobial and antiviral activities, numerous studies have also reported that specific AMPs exhibit significant anti-inflammatory properties. [39][40][41][42] AMPs not only directly inactivate certain potent pro-inflammatory stimuli, such as LPS, effectively inhibiting the release of inflammatory cytokines, 43,44 but also hinder specific proinflammatory signaling pathways to dampen the inflammatory response. 39,45 Consequently, AMPs are especially appealing candidates for the treatment of inflammatory disorders.…”

The Anti-Microbial Peptide (Lin-SB056-1)2-K Reduces Pro-Inflammatory Cytokine Release through Interaction with Pseudomonas aeruginosa Lipopolysaccharide

“…For instance, the stronger LPS-binding affinity of (lin-SB056-1) 2 -K compared to its monomeric counterpart could be explained by its lower susceptibility to the inhibitory effect of different experimental factors (e.g., salts, proteases, macromolecules and/or cellular components) on the establishment of electrostatic interactions [49,50]. Such peptide-LPS interactions could hamper LPS to assume an optimal folding for the binding to its receptors on effector cells with consequent reduction in the pro-inflammatory response [9,51]. Alternatively, as only monomeric forms of LPS are able to trigger cell activation, the dendrimeric peptide could act by inducing LPS aggregation.…”

“…Chronic infection and inflammation are, for example, observed in Pseudomonas aeruginosa lung infections in cystic fibrosis (CF) patients [6]. Hence, due to their dual (anti-bacterial and immunomodulatory) mechanism of action, AMPs are gaining increasing interest for the management of chronic infections [7][8][9][10][11].…”