The severe infection is becoming a significant health problem which threaten the lives of patients and the safety and economy of society. In the way of finding new strategy, antimicrobial peptides (AMPs) - an important part of host defense family, emerged with tremendous potential. Up to date, huge numbers of AMPs has been investigated from both natural and synthetic sources showing not only the ability to kill microbial pathogens but also propose other benefits such as wound healing, anti-tumor, immune modulation. In this review, we describe the involvements of AMPs in biological systems and discuss the opportunity in developing AMPs for clinical applications. In the detail, their properties in antibacterial activity is followed by their application in some infection diseases and cancer. The key discussions are the approaches to improve biological activities of AMPs either by modifying chemical structure or incorporating into delivery systems. The new applications and perspectives for the future of AMPs would open the new era of their development.

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Polybia-MP1 is a well-known natural antimicrobial peptide isolated from the venom of the social wasp Polybia paulista. A recent study showed that this peptide displays a broad antibacterial spectrum as well as low toxicity to human red blood cells and normal fibroblasts. However, its moderate antimicrobial activity and high susceptibility to protease have been a major hurdle for clinical use. This study examined the possibility of developing biologically more potent, yet metabolically more stable, analogues of MP1 using an emerging technology termed "all-hydrocarbon stapling." The stapled analogues of MP1 showed more than a threefold increase in helicity as well as an approximately 70-fold enhancement in proteolytic stability. These stapled analogues also exhibited a significant increase in inhibition against some Gram-positive bacteria while displaying a modest enhancement in hemolytic activity. Overall, the current study demonstrated that the all-hydrocarbon stapling system is a highly useful tool for the development of biologically more potent and metabolically more stable analogues of natural antimicrobial peptides.

The threats of drug resistance and new emerging pathogens have led to an urgent need to develop alternative treatment therapies. Recently, considerable research efforts have focused on membrane-active peptides (MAPs), a category of peptides in drug discovery with antimicrobial, anticancer, and cell penetration activities that have demonstrated their potential to be multifunctional agents. Nonetheless, natural MAPs have encountered various disadvantages, which mainly include poor bioavailability, the lack of a secondary structure in short peptides, and high production costs for long peptide sequences. Hence, an "all-hydrocarbon stapling system" has been applied to these peptides and proven to effectively stabilize the helical conformations, improving proteolytic resistance and increasing both the potency and the cell permeability. In this review, we summarized and categorized the advances made using this powerful technique in the development of stapled MAPs. Furthermore, outstanding issues and suggestions for future design within each subcategory were thoroughly discussed.

We previously reported a de novo design of antimicrobial heptapeptide helices using Verdine's all-hydrocarbon peptide stapling system. One of the important structure-activity relationships we found from these previous studies was that extending of the hydrophobic face by replacing of alanine with leucine in positon 5 increases antimicrobial activity. In this study, to further improve the activity profile of this peptide series, we investigated the substitution effects of position 5 on conformational and proteolytic stability as well as antimicrobial and hemolytic activity. We found that antimicrobial activity and cell selectivity can differ depending on the physicochemical properties of the residue in that specific position. The results shown in this work suggest that the stapled amphipathic heptapeptide helix can serve as a promising platform for developing new antibiotics that can cope with antibiotic resistance problem.