The clinical application of host defense proteins is in full swing

So far, more than 1,000 antimicrobial peptides have been identified and confirmed, and most of them have broad-spectrum anti-G+ bacteria, G- bacteria, viruses, protozoa and/or fungi. These peptides include those with direct antimicrobial activity, those that enhance the immune system to clear or prevent infection, and those that have been rationally improved by sequence modification.

Nonetheless, AMPs have been used as antibiotics for some time. The cationic peptides polymyxin B and gramicidin S are produced by Bacillus polymyxa and Brevibacterium respectively, and have been in the market for external over-the-counter drugs for many years; nisin produced by Lactococcus lactis is put into production as a food preservative .

Nevertheless, the clinical effect of AMPs has been attracting much attention. For example, MX-226/Omeganan has a preventive effect on catheter-related infections, but issues such as its clinical trial design and manufacturing license have been put on hold. Some other AMPs that have completed phase III clinical trials include: pexiganan, a type of bombesin, which mainly prevents foot ulcers caused by diabetes; iseganan, pig protegrin-1, which mainly prevents oral mucositis caused by radiotherapy, but these None of the AMPs has received a new drug application (NDA, new drug application) license. The failure of the application is often not due to lack of activity, but because there is no absolute advantage when compared with existing drugs (eg, cost and benefit are not equal).

So far, clinical trials of AMPs have been mainly limited to external use, with the aim of developing drugs with direct antibacterial activity. Factors such as cost, poor pharmacokinetics due to sensitivity to body proteases and other possible clear mechanisms, and as yet unknown cytotoxicity all limit the potential systemic application of AMPs.

However, the researchers have found solutions to every limitation of AMPs research. Regarding the cost issue, the research target has turned to the recombinant DNA expression strategy to reduce the cost; in addition, the application of peptide array and cash computing strategy and the increase of fatty acyl group make the broad-spectrum antimicrobial peptide fragments smaller. Sensitivity to proteases has been addressed through a range of measures, including formulation, construction of peptidomimetics equivalent to AMPs, and use of D-amino acids or unnatural amino acids.  Taking polymyxin as an example, its cytotoxicity is mainly dealt with by constructing prodrugs (methanesulfonate derivatives), and this explanation scheme also provides a reference for dealing with the cytotoxicity of AMPs

As antibacterial medicine, AMPs have several advantages over antibiotics. Can be used alone or synergistically with other antibacterial medicine, immune regulation / anti-inflammation, or anti-endotoxin; like many conventional antibiotics, AMPs also have broad-spectrum antibacterial activity, but the difference is that, in addition, AMPs also have antiviral and/or antifungal activity;

In addition, the difference between the minimum inhibitory concentrations (MIC, minimal inhibitory concentrations) and the minimum bactericidal concentrations of AMPs is usually less than two times, indicating that AMPs are mostly bactericidal rather than inhibiting bacterial growth and reproduction. More and more research evidence shows that AMPs have multiple targets in pathogenic microbial cells. Due to their amphipathic nature, all AMPs interact directly with G+ and G- and the cytoplasmic membranes of eukaryotic microorganisms, leading to membrane barrier disruption or uptake and inhibition of intracellular targets. Some selective targets include macromolecular synthesis, cell differentiation, cell wall biosynthesis, biosynthesis of macromolecules, and certain heat shock enzymes. This multi-target and interaction with physiological structures makes microorganisms less likely to develop drug resistance. It is also worth noting that at least two AMPs preparations, Omeganan and hLF1-11, have been clinically tested for their immunomodulatory activity.

For all new antimicrobial agents, drug resistance has been a central issue in drug development and clinical application. Although resistance appeared in in vitro tests, it was very weak compared with antibiotics. For example, the drug resistance of Pseudomonas aeruginosa at a 30-fold scale increased 190-fold after the use of the aminoglycoside antibiotic gentamicin (sub-MIC), while the use of synthetic peptides under the same conditions only increased 2-4 times. There is currently no known mechanism by which bacteria develop resistance to a single AMP, possibly because mutations to develop resistance are too costly for bacteria. Indeed, microbial survival requires a balance between resistance to direct microbial killing and innate immune clearance. Interestingly, the antimicrobial activity of AMPs is highly sensitive to divalent cations, serum, and negative macromolecules such as glucosamine, yet still protects the organism under these conditions. Based on this, the immunomodulatory properties of AMPs—cell migration, inventory, differentiation, induction of antimicrobials, and immune regulation—may be more meaningful under physiological conditions.

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There are twelve chapters in Multifunctional Cationic Host Defense Peptides and Their Clinical Applications, This article is serialized as an excerpt: Chapter 3 The Body's Defense Guards - Host Defense Proteins