PAC-113, as well as a new type of Trp-rich peptide, is a 12 amino-acid fragment of the saliva protein histatin 5 and a histidine-rich antimicrobial peptide with the sequence AKRHHGYKRKFH2. In addition, it is originally derived from the human saliva protein histatin 5 and found to possess clinical activity against fungus infections in HIV patients with oral candidiasis. Moreover, PAC-113 showed to have excellent anti-Candida activities. Recently, it has been reported that PAC-113 is safe and effective in the clinical trials for HIV patients with oral candidiasis, which has a good outcome for oral candidiasis therapy. But the activity of PAC-113 is restricted to low-salt conditions, limiting its application. Several studies have reported that the efficacy of PAC-113 is greatly reduced in the presence of high concentrations of salt.
PAC-113 is currently undergoing phase II clinical trial as a pharmaceutical agent to fight against fungal infections in HIV patients with oral candidiasis. Antimicrobial peptides play important roles in the host innate defense mechanism by interacting and permeabilizing microbial membranes. The main microbicidal mechanism of these antimicrobial peptides to fight against bacteria and fungi is to incorporate and permeabilize the microbial membranes, thus causing the destruction of the microbes. Several studies have suggested that the antimicrobial activity of PAC-113 may act not only through binding and destabilization of the microbial membrane, but also through specific protein receptors on the surface of microbial cells. In addition, it has been reported that the activity of PAC-113 against Candida albicans is initiated through cell surface binding, followed by translocation into cell with the help of the Candida albicans cell wall protein Ssa2, which is part of the cell killing effects.
In addition, PAC-113 has been studied in humans with experimental gingivitis, and the results showed that PAC-113 can reduce gingivitis, gingival bleeding, and plaque in humans, and it is safe. On the other hand, the advantages of PAC-113 over the current treatments for oral infectious diseases are obvious due to its safety profile and reduced risk of antibiotic resistance. At the same time, PAC-113 is safe due to its natural origin, which has been demonstrated in previously conducted clinical trials, and the reduced risk of drug resistance is due to its unique mechanism of action. Some data suggest that antimicrobial peptides can be used as novel therapeutic agents.
Pharmacokinetics and metabolism
PAC-113 is safe and may overcome the toxicity and degradation problems. However, the development of antimicrobial peptides has been hindered by several problems. One of these problems is the salt sensitivity.
1. Cheng, K. T., Wu, C. L., Yip, B. S., Yu, H. Y., Cheng, H. T., Chih, Y. H., & Cheng, J. W. (2018). High Level Expression and Purification of the Clinically Active Antimicrobial Peptide P-113 in Escherichia coli. Molecules, 23(4), 800.
2. Yu, H. Y., Tu, C. H., Yip, B. S., Chen, H. L., Cheng, H. T., Huang, K. C., ... & Cheng, J. W. (2011). Easy strategy to increase salt resistance of antimicrobial peptides. Antimicrobial agents and chemotherapy, AAC-00202.
3. Yip, B. S., Chen, H. L., Cheng, H. T., Wu, J. M., & Cheng, J. W. (2009). Solution Structure and Model Membrane Interactions of P‐113, a Clinically Active Antimicrobial Peptide Derived from Human Saliva. Journal of the Chinese Chemical Society, 56(5), 961-966.