Anti-infective activity of apolipoprotein domain derived peptides in vitro: identification of novel antimicrobial peptides related to apolipoprotein B with anti-HIV activity

Abstract

BackgroundPrevious reports have shown that peptides derived from the apolipoprotein E receptor binding region and the amphipathic α-helical domains of apolipoprotein AI have broad anti-infective activity and antiviral activity respectively. Lipoproteins and viruses share a similar cell biological niche, being of overlapping size and displaying similar interactions with mammalian cells and receptors, which may have led to other antiviral sequences arising within apolipoproteins, in addition to those previously reported. We therefore designed a series of peptides based around either apolipoprotein receptor binding regions, or amphipathic α-helical domains, and tested these for antiviral and antibacterial activity.ResultsOf the nineteen new peptides tested, seven showed some anti-infective activity, with two of these being derived from two apolipoproteins not previously used to derive anti-infective sequences. Apolipoprotein J (151-170) - based on a predicted amphipathic alpha-helical domain from apolipoprotein J - had measurable anti-HSV1 activity, as did apolipoprotein B (3359-3367) dp (apoBdp), the latter being derived from the LDL receptor binding domain B of apolipoprotein B. The more active peptide - apoBdp - showed similarity to the previously reported apoE derived anti-infective peptide, and further modification of the apoBdp sequence to align the charge distribution more closely to that of apoEdp or to introduce aromatic residues resulted in increased breadth and potency of activity. The most active peptide of this type showed similar potent anti-HIV activity, comparable to that we previously reported for the apoE derived peptide apoEdpL-W.ConclusionsThese data suggest that further antimicrobial peptides may be obtained using human apolipoprotein sequences, selecting regions with either amphipathic α-helical structure, or those linked to receptor-binding regions. The finding that an amphipathic α-helical region of apolipoprotein J has antiviral activity comparable with that for the previously reported apolipoprotein AI derived peptide 18A, suggests that full-length apolipoprotein J may also have such activity, as has been reported for full-length apolipoprotein AI. Although the strength of the anti-infective activity of the sequences identified was limited, this could be increased substantially by developing related mutant peptides. Indeed the apolipoprotein B-derived peptide mutants uncovered by the present study may have utility as HIV therapeutics or microbicides.

Spotlight on Human LL-37, an Immunomodulatory Peptide with Promising Cell-Penetrating Properties

“…Dermicidin is secreted as a precursor by sweat glands and is activated by cathepsin D [ 10 ]. Some antimicrobial peptides are derived from proteins which have apparently no obvious role in innate immunity as the amyloid beta protein associated with Alzheimer’s Disease [ 11 ], proenkephalin-A [ 12 ], apolipoproteins A, B or E [ 13 , 14 , 15 ], growth factors [ 16 ] or members of the complement system or superoxide dismutase [ 17 ]. After a brief description of defensins and cathelicidins, this review will focus mostly on LL-37, the only human antimicrobial peptide derived from cathelicidin.…”

Induction of the Cpx Envelope Stress Pathway Contributes to Escherichia coli Tolerance to Antimicrobial Peptides

“…The original ApoEdp peptide (sequence, LRKLRKRLLLRKLRKRLL) showed direct, broad anti-infective activity against bacteria and viruses (27). Replacement of all leucine residues with tryptophan amino acids in ApoEdpL-W (sequence, WRKWRKRWWWRKWRK RWW) led to production of a variant with increased potency and high antimicrobial activity against viruses, parasites, and Staphylococcus aureus, despite a slight decrease of antibacterial activity against Pseudomonas aeruginosa (28)(29)(30). To identify bacterial resistance potentially induced upon exposure to antimicrobial peptides, we studied the Escherichia coli genetic response to ApoEdpL-W and demonstrated the contribution of the CpxAR envelope stress signaling pathway to E. coli resistance to ApoEdpL-W and several other antimicrobial peptides.…”

Canine Bone Marrow Mesenchymal Stem Cell Conditioned Media Affect Bacterial Growth, Biofilm-Associated Staphylococcus aureus and AHL-Dependent Quorum Sensing

“…ApoD is an extracellular glycoprotein of the lipocalin protein family, involved in various functions such as immune response, cell proliferation regulation, chemoreception, retinoid metabolism, axon growth and proteolysis regulation [ 46 ].…”