Antimicrobial peptides (AMPs) are primordial in nature. No stranger to plants, mammals and humans, antimicrobial peptides have been found to serve a plethora of purposes. In clinical research, AMPs are effective as anti-infective agents. As well, used in combination of antivirals or antibiotics, they may be used in conjunction with pharmaceuticals to fight against drug resistance. AMPs are also showing promise as topical anti-infective and immuno-stimulating agents. Other clinical trials have resulted in AMP applications for toxin neutralization that prevents death due to bacterial complications such as septic shock.
AMPs are often categorized based on their peptide properties, which include charge, hydrophobicity, and length. Based on net charge, there exist neutral, anionic, and cationic peptides. Based on hydrophobicity, AMPs are hydrophobic, hydrophilic, and amphipathic. In addition, naturally-existing AMPs can be categorized on their peptide sizes, which are ultra-small (2-10 aa); small (10-24 aa); medium (25-50 aa); and large (50-100 aa). AMPs that measure >100 aa are classified as antimicrobial proteins.
Antimicrobial Peptides in Humans
In their essence, antimicrobial peptides (AMPs) function to ameliorate microbes so as to halt growth of pathogenic cell actions. By destroying harmful microbes, AMPs can boost immunological activities of animals, plants and humans.
There are three human AMPs, and they are:
From what researchers understand, each of these work to exert immunomodulation effects on infectious diseases and inflammatory processes in humans.
Human survival has long since been dependent upon AMPs to fend off life-threatening elements such as bacteria, fungi, viruses, and certain parasites. Multi-functioning, diversified antimicrobial peptides guard against destructive pathogens.
Vast in types, AMPs are gene-en-coded and short in structure with less than 100 amino acids. They are amphipathic – with both hydrophilic and hydrophobic parts. They display multiple modes of action that contain the following properties, which are concentration- and sequence-dependent:
The defense mechanisms active in human antimicrobial peptides contain biophysical properties that are similar, however the sequencing in closely-related AMPs are usually unalike. With that said, some AMPs have like patterns of amino acids, or are similar in regions, as is the case of cathelicins in their pro-regions or aconserved regions. This can possibly be due to species’ evolutionary adaptions to certain microbial environments (Boman, 2000).
Taking a revealing look at the three types of human AMPs, the first one is defensins, for which there are two types: β-defensins and α-defensins. β -defensins originated prior to α-defensins and are found in insect defensins. Yang, et. al (2004) determined that α-defensins are present in mammalian copies in single chromosome regions and are expressed in a very limited range of tissues.
Each type of defensins is comprised of 18–45 cationic (positive-charged ions) amino acids that include 6 conserved cysteines and 3 disulfide bonds.
Four types of human defensins can be found in:
• Paneth cells
• Keratinocytes or mucosal cells
• Epithelial cells
In humans, defensins exist in the digestive (gastric antrum), reproductive (testis), respiratory, and urinary systems, as well as in plasma (Duits et al., 2002; Auvynet and Rosenstein, 2009; Lai and Gallo, 2009; Schneider et al., 2005). β -defensins are 36–42 amino acids long peptides with disulfide alignment patterns of 1-5, 2-4, 3-6. They contain a lengthier N-terminal region than do α-defensins. The β-sheet is stabilized by three disulfides, and the parallel structure of the α-defensin disulfide orientation permits flexibility around its short axis. α-defensins are 18-45 amino acids long.
All defensins are fierce and formidable microbes that evoke broad-spectrum antimicrobial activities against fungi, enveloped viruses, and bacteria.
Cathelicidins are characterized by the N-terminal end within the central conserved region as well as a variable C-terminal region (Zanetti et al., 1995;Giuliani et al., 2007). Defensins and cathelicidins can be synthesized in order to activate their propeptide forms. There is only one type of human cathelicidin, and that is the hCAP18 propeptide. It is processed in neutrophils so as to release LL-37 or ALL-38. LL-37 is a 37 amino-acid long peptide with a hydrophobic N-terminal region and C-terminal region that takes on a α-helical formation around negatively charged lipids.
Amphipathic in nature, the LL-37 attaches to bacterial membranes and lipopolysaccharide (LPS). Hence, its properties are conducive to displaying strong antimicrobial activities that flourish in their broad-spectrum capabilities to fend off infections and diseases (Sörensen et al., 2001; Sorensen et al., 2003; de Haar et al., 2006). Cathelicidins are also derived from the human CAP18 protein.
The third group in human antimicrobial peptides is histatins, which are very small peptides that are full of histidine. They are also cationic and are found in human saliva. Histatins create a random-coil conformation within water-based solvents, and α-helical formations within non-water solvents, the latter for which is a commonality to cathelicidins.
As with the aforementioned human dipeptides, also known as human defense peptides (HDPs), histatins work as defense mechanisms within the human immunological system.
Molecular Targets of AMPs
AMPs can be classified in the following two ways when considering their molecular targets, which are:
1. Cell surface targeting peptides, such as nisins and temporins. They target cell-surfaces, attacking membranes and non-membrane peptides. They specifically target cell walls (carbohydrates), membranes (lipids), and receptors (proteins).
2. Intracellular targeting peptides, including pro-rich peptides. Intracellular targeting peptides are further categorized based on their target molecules, such as DNA, RNA and proteins.
AMP Structures & Mechanisms
Unconventional therapeutic treatments have increasingly become an urgent undertaking in clinical trials, though no antimicrobial agents have yet to be approved by the FDA. At any rate, the ability of naturally-occurring antimicrobial peptides to kill multidrug-resistant organisms is a valuable alternative to current drug therapies which are increasingly becoming ineffective due to their resistant properties. The most eminent natural AMPs in humans are defensins and cathelicidins as they are created by immune system cells, while formidable histatins are produced and secreted into human saliva via the salivary glands.
The structures of AMPs, as noted above, are small, positively charged, and amphipathic (containing both hydrophobic and hydrophilic regions). AMPs are classified into four different peptide structures, which are:
The mechanisms of antimicrobial activities work firmly against harmful microbes by disruption of membranes and pore formations, thus permitting strong outflows of critical ions and nutrients. This membrane permeation varies between peptides, depending on various factors such as:
• Peptide concentrations
• Amino acid sequences
• Compositions of membrane lipids
Current research supports the activities of AMPs binding to the cytoplasmic membrane, thus producing micelle-like accumulations, which, in turn, create the disruptive effects of AMPs. Additional research points to evidence whereby intracellular targeting of cytoplasmic elements are present, which are vital for complete cellular physiology. This results in the inhibition of cell-wall biosynthesis as well as DNA, RNA and protein synthesis.
Antimicrobial Peptides: Therapeutic and Pharmacologic Promise
AMPs are also known to contain anti-viral agents, thus inhibiting viral fusion and egress. This process halts infection and the spread of viruses through direct synergy with host-cell surface molecules as well as membranous viral envelopes. These activities, coupled with efficient cell death caused by AMPs make antimicrobial peptides promising candidates for the development and discovery of crucial pharmacologic agents.
In addition to the rapid killing of microbes and their broad-spectrum antimicrobial activities, AMPs have been discovered to neutralize endotoxins while combatting antibiotic resistance. Scientists believe that this is due to the profound changes in membrane structure thought to provide the microbial cell with resistance-type activities.
Despite the biological role of AMPs to be antimicrobial activities, atypical and unique alternative molecular functions of AMPs also include immunomodulatory activities, and wound-healing and anti-neoplastic properties. At present, AMPs are being utilized as models for the development of novel therapeutic agents that may ultimately be used as antimicrobials, inflammation regulators, or for cancer therapies.
With over 800 antimicrobial peptides having been isolated and identified, there is a vast amount of research that still must be conducted on AMP properties. AMPs present an area in its infancy that is much too promising to ignore as it relates to therapeutic and pharmacologic applications.
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