*3.1. CgA-Derived AMPs*

Chromogranin A (CgA) is a glycoprotein with 431 residues and a molecular weight of 49 kDa belonging to the Granin family, discovered for the first time at the end of the 1960s in the granules of adrenomedullary chromaffin cells [32]. In the last few decades, CgA has been identified in immune cells [33–35], neurons [36], cardiomyocytes [37], keratinocytes and fibroblasts [38]. This protein may influence different physiological processes. Its role was reported in cardiac function and cardio-protection [39], catecholamine storage and feedback release [40] and the modulation of vascular function [41] but also in cellular recruitment and the modulation of immune response [32,35,42]. However, this prohormone produces, by proteolytic processing, active biological peptides, such as Vasostatins (Vs), Prochromacin, Chromacin, Pancreastatin, WE 14, Catestatin (Cts), Parastatin and Serpinin [43,44]. At the end of the 1990s and early 2000s, several CgA-derived peptides were discovered as AMPs acting against several bacteria, fungi and yeast. The CgA-derived peptides have been found in biological fluids involved in host-defense responses, such as serum, saliva and neutrophils secretions, or against pathogens in the first barrier of the human body, such as the skin [33,34,38,45,46]. The CgA-derived peptides act as antimicrobial agents in the micro-molar range [33,46–48]. These concentrations are also reported in the biological fluid after stimulation with pathogen toxins or during infection [33,34,42,46]. Among the CgA-derived peptides, the Vs-I and Cts were first identified as antimicrobial agents; however, their antimicrobial domains were rapidly reported. Vs-I was initially identified as a vasoinhibitory agent [49]. For Vs-I, Lugardon characterized this peptide's antimicrobial activities against many pathogens [33,47,50]. However, after the incubation of Vs-I with endoproteinase Glu-C, a digested sequence CgA47-66, called Chromofungin (Chr), was identified and found highly active against several fungi and yeasts [47]. It has a global hydrophobicity and amphipathic character, allowing a strong interaction with the membrane. Specifically, Chr possesses a positive charge of +3.5, showing an amphipathic helix in the C-terminal part in the sequence CgA53-66 and at the N-terminal domain, a hydrophobic sequence corresponding to CgA48-51 and a hydrophilic structure CgA53-46, respectively [47,51]. The Vs-I and Chr antimicrobial mechanism of action is explained through the specific interaction of peptides with ergosterol, one of the main components of yeast and fungal membranes, inducing increased pressure and penetration into the membrane [47,51] (Figure 1). Other data demonstrated that Chr could inhibit Calcineurin activity by interacting with Calmodulin [47] (Figure 1). Within microbial cells, Vs-I and Chr may interfere with the Calcium/Calmodulin/Calcineurin signaling pathway by blocking the pathway implicated in virulence and skeleton development of cell walls [52]. Cts was identified as a catecholamine release-inhibitory peptide [53]. Cts is a small 21-amino-acid cationic peptide with a positive net charge of +5 within the bovine sequence (bCgA344-364) possessing a C-terminal hydrophobic sequence. Taylor and colleagues identified a smaller peptide (CgA344-358) derived from Cts with a more substantial inhibitory effect on catecholamine release [54]. This peptide was called Cateslytin (Ctl) by Briolat et al. and is also characterized by its antimicrobial activities with potent effects compared to Cts [46]. Ctl is also a positively charged (+5) arginine-rich antimicrobial peptide and, in an aqueous solution, is a linear peptide with a disordered structure. However, when interacting with the membrane, Ctl acquires an α-helical form [55]. Other studies with a system mimicking bacterial membrane demonstrated that Ctl could convert its structure into antiparallel β-sheets precipitating against the negatively charged part of the membranes [56]. Then, Ctl induced an increased rigidity, permeability gradient and membrane pore formation in the domains containing ergosterol [56–58] (Figure 1).
