Medical Applications of Antimicrobial Peptides

Antimicrobial peptides mainly carry out non-specific rapid killing and intracellular interference on the cell membrane of harmful pathogens and do not target specific molecular pathways, which greatly reduces the probability of bacterial resistance to antimicrobial peptides.Therefore, it is of great significance to apply antimicrobial peptides to the clinical research of antimicrobial drugs. In most cases, antimicrobial peptides themselves are often used as active ingredients (not carriers) of antibacterial and anti-inflammatory drugs, which can be used for research and testing with the ultimate purpose of human treatment by smearing or injection. Currently, Daptomycin, Vancomycin, Dalbavancin (BI397,Dalvance, Xydalba), and Colistin have been approved by the US Food and Drug Administration (FDA) for antimicrobial therapy in the form of intravenous injection. Several other antimicrobial peptides are under clinical development. In addition to their initial antibacterial effects, more and more antimicrobial peptides show multiple functions, including anti-cancer, immunomodulatory, antiviral, and anti-parasitic, etc. They also begin to be combined with medical biomaterials to serve medical tissue engineering, drug delivery, and medical cosmetology. These attempts open up a new field of application for antimicrobial peptides.

Applications of Antimicrobial Peptides Antimicrobial peptides for antibacterial and anti-inflammatory drugs Most antimicrobial peptides have been developed as potential antibacterial and anti-inflammatory drugs. Bacteriocin is a kind of cationic antimicrobial peptide formed by 30~60 amino acid residues isolated from bacteria. Nisin, a member of the family, has high antibacterial activity against a variety of gram-positive and even gram-negative bacteria, and can also control the growth of enterotoxigenic Escherichia coli in combination with cinnamaldehyde and Ethylenediaminetetraacetic acid (EDTA).

In addition to antibacterial activity, some antimicrobial peptides can also directly or indirectly participate in host immune regulation and protect the host from infection. Defensin is another big family of antibacterial peptides widely existing in neutrophils, macrophages, lymphocytes, NK cells, and other immune cells, and has a strong pro-inflammatory function. Human defensin HBD2, HBD3, and HBD4 can stimulate the expression of IL-6, IL-10, and other immune factors in human keratinocytes. These defensins are also found to induce intracellular signaling molecules involved in keratinocyte migration and proliferation, such as EGFR, STAT 1, and phosphorylated STAT3, and promote keratinocyte migration and proliferation to participate in wound healing.

Antimicrobial peptides for antiviral drugs In addition to anti-inflammation and immune regulation, some antimicrobial peptides have broad-spectrum resistance to viruses, typically LL-37. Barlow et al. evaluated that LL-37 could reduce the disease severity and viral replication ability of influenza virus-infected mice, and its therapeutic effect was similar to that of the specific antiviral drug Zanamivir. Tripathi et al. found that LL-37 could directly destroy the membrane structure of the influenza virus to achieve virus suppression. LL-37 also inhibited other viruses with membranous structures, such as human immunodeficiency virus (HIV), vaccinia virus, herpes simplex virus, and Dengue virus. In addition, Todorov et al. isolated a novel broad-spectrum antimicrobial peptide with the size of 3950 Da, which was resistant to herpes simplex virus, poliovirus, and measles virus while inactivating many harmful bacteria. Recent studies have also shown that the antimicrobial peptide Nisin can also interact with cell receptors targeted by the spike protein of the novel coronavirus SARS-CoV-2, opening up the prospect of using AMPs against the novel pandemic coronavirus.

Antimicrobial peptides for anti-parasitic drugs Reports on anti-parasitic antimicrobial peptides are rare, mostly focusing on anti-plasmodium, anti-leishmania, and anti-Trypanosoma. Halictine-2, Dragomide E, Temporin-Sha, BmajPLA2-Ⅱ, and other antimicrobial peptides from different sources have strong anti-leishmania abilities. In addition, Lc-P5L4 from Larimichthys crocea can stimulate the cell membrane rupture of the Marine fish parasite Cryptocaryon. LZ1, a peptide derived from snake antimicrobial peptide, can strongly inhibit plasmodium falciparum in blood by specifically inhibiting the production of adenosine triphosphate (ATP) in plasmodium-infected red blood cells.

Antimicrobial peptides for anti-cancer drugs Some antimicrobial peptides were also found to be resistant to some cancer cells and could be used as potential new anti-cancer drugs. Compared with normal cells, the anion composition on the surface of the cancer cell membrane is the specific target of an antibacterial peptide attack. Antimicrobial peptides are more likely to disengage from the surface of the cancer cells and selectively kill cancer cells through electrostatic action, but most antimicrobial peptides prefer to regulate the metabolic pathways or cytokines of cancer cells to achieve the anti-cancer effect.

Antimicrobial peptides for medical tissue engineering To avoid immunogenicity and other factors, most of the antimicrobial peptides applied in the field of medical tissue engineering are LL-37 derived from human and human defensin, and most of them are chemically fixed or physically mixed with various medical devices, internal implants, drug carriers, medical consumables, and trauma dressings. At present, tissue engineering scaffolds combined with antimicrobial peptides have been used in the repair of bone, teeth, skin, cornea, and many other organs and tissues.

Additionally, LL-37 also plays an important role in cell migration, cytokine production, apoptosis, and angiogenesis. In vitro and in vivo studies of mesenchymal stem cells and LPS-induced mouse cranial lytic bone defect models showed that LL-37 effectively inhibited LPS-induced osteoclast formation and harmful bacterial activity in vitro. Similarly, the functionalization of bone morphogenetic protein-2 (BMP-2) and ponericin G1 of the three-dimensional PLGA porous scaffold can be achieved by polydopamine coating. The scaffold can effectively regulate the osteogenic differentiation of preosteoblasts and inhibit pathogenic microorganisms at the same time, thus increasing biological activity. In addition to PLGA, the antimicrobial peptide LF1-11 can also be modified on the titanium alloy surface implant, which not only greatly improves the adhesion ability of mesenchymal stem cells (due to the addition of RGD sequence) but also has an effective antibacterial effect on Staphylococcus aureus.

Antimicrobial peptides for drug delivery systems Since most antimicrobial peptides are proteins or peptides in nature, they are easy to be degraded by proteases during drug administration and some antimicrobial peptides have non-specific cytotoxicity, which can inhibit or even kill tumor cells and normal cells at the same time, limiting the clinical promotion of this kind of antimicrobial peptides. Therefore, by drug delivery system, nano-sized carriers can be used to load concentrated antimicrobial peptides to reduce the release of drugs during transportation and avoid protease degradation to a certain extent, improving the resistance and targeting ability of some antimicrobial peptides to cancer cells, bacteria or fungi. At present, the nanocarriers combined with antimicrobial peptides include biodegradable biomolecules, liposomes, and non-degradable magnetic nanoparticles.

Antimicrobial peptides for skin care and medical beauty Some antimicrobial peptides can induce endothelial cell growth, promote the secretion of angiogenic factors, weaken vascular atrophy caused by aging, and accelerate wound healing after skin injury. For example, LL-37 induces endothelial cell proliferation, migration, and tubular formation through LPS and macrophage activation, increasing vascularization and re-epithelialization. AG-30 can induce the growth of endothelial cells and secrete angiogenic factors, which can reduce the decrease of blood vessels caused by aging so that the skin can obtain adequate nutrition. DRGN-1 can also be used to accelerate wound closure by cleaning the biofilm of infected bacteria and promoting keratinocyte migration and proliferation to form effective tissue regeneration without scars. CopA3 can inhibit the ability of dermal fibroblasts to secrete procollagen type Ⅰ caused by ultraviolet radiation and reduce skin aging. Therefore, antibacterial peptides play a role in the treatment of many skin diseases such as melanoma, acne, diabetic foot ulcer, and psoriasis, and can also be used as an additive for new skincare cosmetics.

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