Background: Sunflower trypsin inhibitor-1 (SFTI-1) and Momordica cochinchinensis trypsin inhibitor-II (MCoTI-II) are potent protease inhibitors comprising a cyclic backbone. Results: Elucidation of structure-activity relationships for SFTI-1 and MCoTI-II was used to design inhibitors with enhanced inhibitory activity. Conclusion: An analog of MCoTI-II is one of the most potent inhibitors of matriptase. Significance: These results provide a solid basis for the design of selective peptide inhibitors of matriptase with therapeutic potential.

Cyclotides are bioactive macrocyclic peptides from plants that are characterized by their exceptional stability and potential applications as protein engineering or drug design frameworks. Their stability arises from their unique cyclic cystine knot structure, which combines a head-to-tail cyclic peptide backbone with three conserved disulfide bonds having a knotted topology. Cyclotides are ribosomally synthesized by plants and expressed in a wide range of tissues, including leaves, flowers, stems and roots. Here we describe recent studies that have examined the biosynthesis of cyclotides and in particular the mechanism associated with post-translational backbone cyclization.

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The main bacterium associated with skin infection is Staphylococcus aureus, occurring especially in infections acquired via surgical wounds, commonly leading to lethal hospital-acquired infections, emphasizing the importance of identifying new antimicrobial compounds. Among them, cyclotides have gained interest due to their high stability and multifunctional properties. Here, cycloviolacin 2 (CyO2) and kalata B2 (KB2) were evaluated to determinate their anti-staphylococcal activities using a subcutaneous infection model. Anti-staphylococcal activities of 50mM for KB2 and 25mM for CyO2 were detected with no cytotoxic activities against RAW 264.7 monocytes. In the in vivo assays, both cyclotides reduced bacterial load and CyO2 demonstrated an increase in the phagocytosis index, suggesting that the CyO2 in vivo anti-staphylococcal activity may be associated with phagocytic activity, additionally to direct anti-pathogenic activity.

Staphylococcus aureus is a virulent pathogen that is responsible for a wide range of superficial and invasive infections. Its resistance to existing antimicrobial drugs is a global problem, and the development of novel antimicrobial agents is crucial. Antimicrobial peptides from natural resources offer potential as new treatments against staphylococcal infections. In the current study, we have examined the antimicrobial properties of peptides isolated from anuran skin secretions and cyclized synthetic analogues of these peptides. The structures of the peptides were elucidated by nuclear magnetic resonance (NMR) spectroscopy, revealing high structural and sequence similarity with each other and with sunflower trypsin inhibitor 1 (SFTI-1). SFTI-1 is an ultrastable cyclic peptide isolated from sunflower seeds that has subnanomolar trypsin inhibitory activity, and this scaffold offers pharmaceutically relevant characteristics. The five anuran peptides were nonhemolytic and noncytotoxic and had trypsin inhibitory activities similar to that of SFTI-1. They demonstrated weak in vitro inhibitory activities against S. aureus, but several had strong antibacterial activities against S. aureus in an in vivo murine wound infection model. pYR, an immunomodulatory peptide from Rana sevosa, was the most potent, with complete bacterial clearance at 3 mg · kg ؊1 . Cyclization of the peptides improved their stability but was associated with a concomitant decrease in antimicrobial activity. In summary, these anuran peptides are promising as novel therapeutic agents for treating infections from a clinically resistant pathogen. Staphylococcus aureus is one of the most virulent and opportunistic pathogens, causing increasing numbers of nosocomial and community-acquired infections, and is a leading cause of skin and soft tissue infections (1-3). These Gram-positive cocci produce a myriad of virulence factors that allow the bacteria to attach to host cells, to invade tissues, to evade the host immune system, and to release an array of exoproteins and toxins (4, 5). Contagious S. aureus skin infections can lead to severe muscle or bone infections that ultimately can spread to the lungs or heart (6). The primary treatment involves prescription of ␤-lactam antibiotics such as penicillins and cephalosporins, along with clinical woundcleaning procedures (6, 7). Strains resistant to antibiotics have been emerging since the 1960s, however, especially methicillinresistant S. aureus (MRSA), which is most common in nosocomial skin infections (8). Alarmingly, there have been reports of S. aureus strains that are resistant to the drug of last resort, vancomycin (9).Antimicrobial peptides are now recognized as novel alternative therapeutic agents for infection control (10). Several hypotheses have been examined regarding the mode of action of antimicrobial peptides, including autolysin activation, lipopolysaccharide (LPS) permeabilization, fatal depolarization of the energized bacterial membrane, formation of barrel-stave pores that cause leakage of...