Targeted Antimicrobial Peptides

stances, contributing to the mechanisms of host defenses, has been recognized since the late nineteenth century. In 1963, the in vitro antibacterial activity of leukocyte extracts was attributed to basic proteins. Since the late 1980s, cationic peptides with antimicrobial properties have been subsequently identified in other host cells and tissues and in virtually every living species (Lehrer, 2004). The properties of these “Nature’s antibiotics” and their multiple functions in host defenses of multicellular organisms support the rationale of developing entirely novel peptide-based therapeutics harnessing the effector mechanisms of innate immunity (Hancock and Sahl, 2006). The term antimicrobial peptides covers different forms of natural macromolecules; ribosomally synthesized and non-post-translationally modified innate immunity peptides, or their synthetic analogs, are predominantly considered here. Their antimicrobial and immunomodulatory activities will not be dissociated in general and they will be indistinctively described as (cationic) antimicrobial or host defense peptides. The main assets of innate immunity peptides originate from their primary activity essentially directed at a universal nonprotein target, the bacterial membrane, reinforced by a polypharmacology which includes multiple immunomodulatory and anti-inflammatory activities (Zasloff, 2002; Finlay and Hancock, 2004). Other distinctive and attractive properties in a clinical context comprise their low susceptibility to classical mechanisms of drug resistance, associated with a low propensity to select resistant mutants, their ability to reduce both biofilm and planktonic bacterial counts and to interact with dividing and non-dividing cells by generally targeting a conserved structure which is independent of the proliferative status of the cells (Peschel and Sahl, 2006; Chen et al., 2011; Fjell et al., 2012). Although some mechanisms of bacterial resistance to antimicrobial peptides have been identified, their emergence occurs at significantly lower frequencies than for traditional antibiotics (Peschel and Sahl, 2006). Furthermore, host defense peptides can also act synergistically with these classical antibiotic agents (Giacometti et al., 2000). Innate immunity peptides are therefore a prospective source of antibiotic candidates with extended clinical lifetimes. They have not been approved for clinical use to date, but have progressed toward commercial development through recent technological advances. About 1,200 to 1,700 antimicrobial peptide sequences have been identified and/or predicted to date. Approximately 15 different peptide-based therapeutic agents are currently in clinical trials for anti-infective and/or anti-inflammatory indications, generally limited to topical administration (Fjell et al., 2012; Yount and Yeaman, 2012). The challenges traditionally associated with the clinical development of host defense peptide candidates for systemic therapies require notably solutions addressing the question of possible toxicity. Owing to their rapid metabolic degradation and/or excretion, high doses of these peptides might be required to maintain therapeutic levels in vivo. This may correlate with an improper margin of safety, despite their selectivity for bacterial over mammalian cells (Zasloff, 2002). In addition, the issue of potential immunogenicity should be considered (Mader and Hoskin, 2006). Other concerns may be raised, either inherent to all peptide-based drug candidates, such as low oral bioavailabilities and elevated cost of production, or specific to host defense peptides, in particular their complex pharmacology which could result in uncontrolled off-target toxicity (Pauletti et al., 1997; Hancock and Sahl., 2006; Brown et al., 2007). Peptide therapeutics are capturing an increasing fraction of the global pharmaceutical pipeline. Advances in peptide modification, formulation, and delivery technologies can overcome some of their pharmacokinetic, bioavailability, and toxicity shortcomings and likewise have been applied to innate immunity peptides. The latter have been modified by either optimizing the length and content of their sequences, to increase their selective antibacterial activity, or by conversion into peptidomimetics, to improve their pharmacokinetic properties. In the first case, minimizing the length of the sequence and systematically substituting each residue with other coded amino acids, can yield peptide candidates with improved antibacterial activity and/or increased activity differentials between prokaryotic and eukaryotic (generally erythrocytes) cells. This work has been performed in parallel with structure activity relationship studies for the rationale design of therapeutic candidates (Fjell et al., 2012). It focused on the direct antibacterial activity of some selected candidates, but immunomodulatory peptides devoid of in vitro antimicrobial activity have also been optimized (Hancock et al., 2012). In the second case, peptidomimetics, structures departing from the traditional peptide backbone and/or stereochemistry but reproducing the biological activity of the parent sequence, have been generated as candidates resistant to proteolysis. They include sequences assembled from non-natural amino acids (e.g., Dor Targeted antimicrobial peptides