Antimicrobial peptides: The ancient arm of the human immune system

Abstract

The production of peptides and small proteins with microbicidal activity collectively called antimicrobial peptides (AMPs) is commonly considered to be a primitive mechanism of immunity and has been extensively studied in insects and other non-vertebrate organisms. In addition, a variety of AMPs present in amphibian skin secretion has been well characterised. There is now increasing evidence that AMPs play a crucial role in human immunity as well. Virtually all human tissues and cells typically exposed to microbes are able to produce AMPs. Important AMPs belonging to two structurally distinct classes, known as the defensins and the cathelicidins, are mainly produced by epithelial cells and neutrophils. AMPs significantly contributing to the chemical skin barrier are represented by dermcidin, psoriasin and RNase 7. The antimicrobial activity of saliva largely depends on histidine-rich AMPs known as histatins. Many more, in part less well-known AMPs and AMP-like proteins exist that exhibit various additional functions, apart from their antimicrobial properties. Among them, the neutrophil granule proteins azurocidin and cathepsin G are members of a family of serine-protease homologues called serprocidins and play a role in the regulation of the immune response and degradation of extracellular matrix proteins respectively. As another AMP-like protein of the neutrophil granule content, bactericidal/permeability increasing protein (BPI) is both able to permeabilise bacterial membranes and to function as an opsonin. The whey acidic protein (WAP) domain containing class of AMPs, including secretory leukocyte protease inhibitor (SLPI), elafin and trappin-2, is equally important in inhibition of neutrophil serine proteases and killing of microbes. Certain CC or CXC chemokines are known to possess antimicrobial properties and therefore are called kinocidins. Several kinocidins, including thrombocidin-1 and -2, are contained in the ?-granules of platelets. A cytoplasmic AMP described as ubiquicidin turned out to be identical with the strongly basic ribosomal protein S30. Proteolytic cleavage of the histone protein H2A in the stomach gives rise to an AMP initially described as buforin I. Adrenomedullin is a hormone-like AMP exhibiting vasodilatory and hypotensive effects. Lysozyme is mainly known for its cell wall degrading activity, but is also capable of non-enzymatic killing of bacteria. An iron-binding protein present in milk and other secretions named lactoferrin was shown to possess antimicrobial and antiviral activity and has been implicated in protection against cancer. Clinical studies on the treatment of infectious diseases have been performed with artificial peptides derived from human lactoferrin, histatins and BPI in addition to porcine protegrins, frog magains and bovine indolicidin. Omiganan, representing an indolicidin derivative, has been demonstrated to be effective in the treatment of acne and catheter-related local infections and is currently considered to be the most promising AMP-based drug candidate

Role of Cysteine Residues and Disulfide Bonds in the Activity of a Legume Root Nodule-specific, Cysteine-rich Peptide

“…Why Is the NCR247 [1][2][3][2][3][4] Peptide Unstable?-Our analysis showed that the NCR247 1-2,3-4 peptide remained stable after storage at ϩ4°C in the lyophilized form and Ϫ20°C when dissolved in water, providing further evidence that this is the naturally folded, stable state of the peptide. In contrast, although a single pure RP-HPLC peak was found for freshly synthesized NCR247 1-3,2-4 peptide, after storage, we observed multiple RP-HPLC peaks indicative of an unstable peptide.…”

“…RP-HPLC of the freshly synthesized and folded NCR247 1-3,2-4 peptide showed one major peak, indicating the presence of one pure peptide species (data not shown), as had been observed previously for newly prepared NCR247 1-2,3-4 (11). However, upon storage of the lyophilized peptide preparations, RP-HPLC of NCR247 1-3,2-4 resulted in multiple peaks whereas one major peak was still observed for NCR247 [1][2][3][4] (Fig. 2B).…”

“…2E). Combined, these findings showed that Full-length Peptide Is Important for Full Activity of NCR247 against S. meliloti-To gain insights into the importance of cationic residues for the activity of NCR247 against S. meliloti, we commercially synthesized two truncated versions of this peptide, NCR247 [1][2][3][4][5][6][7][8][9][10][11][12] (lacking the last 12 amino acids from the C-terminal end) and NCR247 [13][14][15][16][17][18][19][20][21][22][23][24] (lacking the first 12 amino The forward scatter (FSC) was measured to estimate relative bacterial cell size, and the PI fluorescence was measured to estimate the relative bacterial DNA content. C indicates number of chromosome copies.…”

“…The antimicrobial activities of mammalian AMPs against microorganisms have been investigated extensively (1,3,4). The root nodules of certain legumes have been found to produce a large family of novel nodule-specific cysteine-rich (NCR) peptides.…”

Invariant Gly Residue Is Important for α-Defensin Folding, Dimerization, and Function

“…They are found throughout the tree of life (1,2). Taking advantage of the protein scaffold and the cellular equipment of transcription and translation, over evolutionary time scales antimicrobial peptides are mutable and often quite versatile, acquiring new functions as they strive to keep the host free from invaders (3).…”