Antimicrobial Peptides

The term antimicrobial peptide is descriptive for a peptide with antimicrobial properties. A variety of AMPs has been isolated from species of all kingdoms and are classified based on their structure and amino acid motifs. Figure 1 gives an overview about the classification of AMPs and their structures. Beside the broad antimicrobial spectrum AMPs have multiple roles as mediators of inflammation with impact on epithelial and inflammatory cells influencing diverse processes such as cell proliferation, immune induction, wound healing, cytokine release, chemotaxis and protease-antiprotease balance and angiogenesis[1]. AMPs qualify as prototypes of innovative drugs that may be used as antimicrobials, anti-lipopolysaccharide drugs, modifiers of inflammation or as treatment of cancer by direct cytotoxic activity or alteration in angiogenesis[2]. The role of AMPs as endogenous antibiotic is documented in animal models with deleted or overexpressed peptides genes[3-5]. In conclusion, AMPs appear to be multifunctional molecules that have their role in host defense and innate immunity. Cathelicidins and defensins are prototypical families of AMPs present in humans. Molecules from both families have been implicated in angiogenesis. Their properties are summarized in the next paragraph.

p-Defensin Cathelicidin

Exon 1 Exon 2 Exon 1 Exon 2 Exon 3 Exon 4

p-Defensin Cathelicidin

Exon 1 Exon 2 Exon 1 Exon 2 Exon 3 Exon 4

Figure 1. Structure of prototypical antimicrobial peptides. Genes, mRNAs, and proteins of defensins and cathelicidins are displayed. Both genes have at least 2 exons. The primary translation product is the pre-pro peptide. After cleavage, the C-terminus represents the molecule with the antimicrobial activity. The complete role of the pre-pro part is not completely understood but may be involved in the folding of the peptide

Figure 1. Structure of prototypical antimicrobial peptides. Genes, mRNAs, and proteins of defensins and cathelicidins are displayed. Both genes have at least 2 exons. The primary translation product is the pre-pro peptide. After cleavage, the C-terminus represents the molecule with the antimicrobial activity. The complete role of the pre-pro part is not completely understood but may be involved in the folding of the peptide

1.1. Defensins

Mammalian defensins are cationic, relatively arginine rich nonglycosylated peptides with a molecular weight of 3,5-4,5 kDa and contain six cysteines that form three characteristic intramolecular disulfide bridges[6]. According to the spacing of the cysteines, the alignment of the disulfide bridges and the overall molecular structure, the defensins can be divided into three subclasses: a-defensins, 6-defensins and 0-defensins. a-defensins are 29-35 amino acids in length, contain three disulfide bridges in a 1-6, 2-4, 3-5 alignment and reveal a triple stranded 6-sheet structure with a 6-hairpin which contains cationic amino acids. The peptides are also known as human neutrophil peptides (HNPs). HNP-1 to -4 are found in azurophil granules of neutrophils where they constitute up to 50% of the total protein present. HNP-5 and -6 have been identified in Paneth cells in the crypts of the small intestinal mucosa and also in the female reproductive tract. 6-defensins are 36-42 amino acids in length reveal a disulfide alignment of 1-5, 2-4, 3-6 and have been isolated from many species. P-defensins are typically expressed in epithelial tissues and are also found in immune cells such as macrophages or lymphocytes[7-11].

1.2. Cathelicidins (LL-37/hCAP-18, CRAMP, PR-39)

Cathelicidins are characterized by a conserved N-terminal cathelin domain and a variable C-terminal antimicrobial domain that can be released from the precursor protein after cleavage by proteinases[12]. LL-37 is the C-terminal part of the only human cathelicidin identified to date called human cationic antimicrobial protein (hCAP-18). The peptide was first isolated from polymorphonuclear leukocytes but is also expressed by lymphocytes, macrophages and epithelial cells. LL-37 is activated when proteinase 3 cleaves its precursor, hCAP-18. LL-37 has antimicrobial activities against gram-positive and gram-negative bacteria, capsuled viruses und fungi (12-15). Beside the antimicrobial abilities it was shown that LL-37 further modulates different inflammatory and immune processes including chemo-taxis of neutrophils and macrophages, epithelial cell activation, tumor growth, and modulation of the function of dendritic cells[16]. LL-37 induced the repair of epithelial wounds of the skin[17] and the lung epithelium[18]. CRAMP is the homologous molecule present in mice. Mice deficient in CRAMP were found to be more susceptible to bacterial infections of the skin[3] and the urinary tract. PR-39 is a porcine proline-rich, 39-amino acid protein of the cathelicidin family for which no obvious homologue exists in humans[19].

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