Antimicrobial Peptidomimetics: Reinterpreting Nature to Deliver Innovative Therapeutics

PALETTE OF EXTRAORDINARY COLORS Virtually all multicellular organisms must ward off pathogenic microbes in order to survive and thrive on this planet. To accomplish this, most metazoans rely on geneencoded antimicrobial peptides (AMPs) as an essential part of their innate immune system. The role played by AMPs – and by the other umoral and cellular components of innate immunity – is particularly crucial in those organisms (the vast majority) that have not developed the more sophisticated adaptive immune system. Even in higher vertebrates as humans, AMPs like defensins and cathelicidins (e.g., LL-37) do not only have direct microbicidal activity, but they also serve as signals which initiate, mobilize, and amplify adaptive immune host defenses, thus functioning as immunomodulatory and immunostimulatory elements (Giuliani and Rinaldi, 2010). Despite a bewildering variety in their primary sequences, AMPs generally share a cationic character, a length that usually does not exceeds 50 residues (a large proportion of which are generally hydrophobic), and a globally amphipathic fold, with clearly distinguishable hydrophilic and hydrophobic faces. These structural features reflect their mode of action, which is primarily directed to the interaction with and damage of the pathogen cell’s plasma membrane, although the evidence that many AMPs may hit other targets is rapidly increasing. These evolutionarily conserved molecules display a broad spectrum antimicrobial activity against bacteria, fungi, protozoans, and even enveloped viruses. AMPs represent key components especially at epithelial surfaces, where the initial contact with pathogens takes place, thus being deployed at the very front line of the defense system, where rapid action is required before the more slowly responding adaptive immune system (if any) can be brought into action. With the prospects of an ever-increasing bacterial resistance to conventional antibiotics looming at the horizon, much attention has been devoted to AMPs as a potential source of new anti-infective drugs (Mangoni, 2011; Yeung et al., 2011). However, despite intense research aimed at spotting possible ways for harnessing the therapeutic potential of these intriguing natural compounds, little practical outcome has been generated as yet. Multiple hurdles on this way exist, indeed, related to the fact that naturally occurring AMPs present serious drawbacks that limit their development into clinically applicable antibiotics. These include (but are not limited to) high costs of manufacture, susceptibility to protease degradation, reduced activity in the presence of salts as those present in serum. In addition, given the recognized immunomodulatory and immunostimulatory effect of several AMPs – that is some cases is so evident that the term Host Defense Peptides has been proposed as more indicative of the real role played by these molecules in vivo – using AMPs systemically to treat infections should necessarily suppose an advanced knowledge of (and possibility to control) the possible responses these peptides can trigger. Furthermore, as mentioned before, AMPs have been crafted by evolution to be part of the network of interacting and self-reinforcing components of the innate immune systems, thus expecting that they could stand alone as the new “magic bullet” against resistant microbes would be simply overoptimistic. Given the inherent limitations of naturally occurring AMPs that have so far prevented their transformation into therapeutics, two general approaches have emerged to overcome this major obstacle, i.e., the modification of existing peptide sequences or the de novo synthesis of peptides, and the development of synthetic molecules that mimic the properties and activities of AMPs (Giuliani et al., 2008; Brogden and Brogden, 2011; Fjell et al., 2011; Giuliani and Rinaldi, 2011). Here, a few recent, significant examples pertaining to these research avenues will be highlighted.