Human apolipoprotein E as a reservoir of cryptic bioactive peptides: The case of ApoE 133‐167

Abstract

Bioactive peptides derived from the receptor-binding region of human apolipoprotein E have previously been reported. All these peptides, encompassing fragments of this region or designed on the basis of short repeated cationic sequences identified in the same region, show toxic activities against a broad spectrum of bacteria and interesting immunomodulatory effects. However, the ability of these molecules to exert antibiofilm properties has not been described so far. In the present work, we report the characterization of a novel peptide, corresponding to residues 133 to 167 of human apolipoprotein E, here named ApoE (133-167). This peptide, besides presenting interesting properties comparable with those reported for other ApoE-derived peptides, such as a direct killing activity against a broad spectrum of bacteria or the ability to downregulate lipopolysaccharide-induced cytokine release, is also endowed with significant antibiofilm properties. Indeed, the peptide is able to strongly affect the formation of the extracellular matrix and also the viability of encapsulated bacteria. Noteworthy, ApoE (133-167) is not toxic toward human and murine cell lines and is able to assume ordered conformations in the presence of membrane mimicking agents. Taken together, collected evidences about biological and structural properties of ApoE (133-167) open new perspectives in the design of therapeutic agents based on human-derived bioactive peptides.

The role of full-length apoE in clearance of Gram-negative bacteria and their endotoxins

“…Research in the field of lipoproteins has the potential to discover new host defense molecules and the mechanisms by which they participate in the immune response to infection ( 12 , 13 , 23 , 32 ). Several in vitro studies have shown that prototypic peptides with the sequence corresponding to the apoE receptor-binding region have strong antimicrobial activity ( 15 , 16 , 17 , 19 , 33 ). In addition, in vivo studies have revealed that apoE is a protein with anti-inflammatory ( 34 , 35 , 36 , 37 ) and anti-infective properties, showing that apoE-deficient mice exhibited an increased susceptibility in response to Gram-negative or fungal infection ( 38 , 39 ).…”

“…More recently, various peptides from the receptor-binding region of apoE (amino acid residues 130–150), which is essential for its biological function in lipid metabolism, have been shown to exert both antiviral and antibacterial activity ( 14 , 15 , 16 , 17 ). This region is responsible for the binding of apoE to the LDL receptor family, and also, within this sequence, residues 142–147 (the heparin-binding domain) mediate attachment of apoE to cell surfaces ( 18 ).…”

“…This region is responsible for the binding of apoE to the LDL receptor family, and also, within this sequence, residues 142–147 (the heparin-binding domain) mediate attachment of apoE to cell surfaces ( 18 ). In particular, some apoE-derived peptides were shown to be effective against multiresistant bacteria and reduced lipopolysaccharide (LPS)-induced storm of cytokines in THP-1 cells ( 16 , 17 ). Therefore, in addition to their anti-infective activity, these peptides also show immunomodulatory activity ( 19 ).…”

Cathelicidins: Immunomodulatory Antimicrobials

“…More recently, computational approaches combining characteristic features of length, charge, and hydrophobicity has led to discovery of protein subdomains which could have the same functions as natural cationic HDPs [ 41 , 42 , 43 ]. For example, a region in the poorly characterized human protein 11-beta-hydroxysteroid dehydrogenase type 3 (HSD 3) showed many HDP-like characteristics, including anti-biofilm and LPS-neutralizing effects [ 42 ].…”

Cryptides Identified in Human Apolipoprotein B as New Weapons to Fight Antibiotic Resistance in Cystic Fibrosis Disease

“…Here, we analyze for the first time the antimicrobial and anti-biofilm properties of two recently characterized AMPs [33] towards Pseudomonas and Burkholderia strains clinically isolated from CF patients. AMPs under test have been identified in human apolipoprotein B (ApoB) by using a bioinformatic method developed by our research group [33][34][35][36][37][38][39][40][41]. Indeed, it is increasingly evident that eukaryotic proteins, with functions not necessarily related to host defense, act as sources of "cryptic" bioactive peptides released upon proteolytic processing by bacterial and/or host proteases [42][43][44].…”