Chemical mimics with systemic efficacy.

Abstract

Host-derived cationic antimicrobial peptides (AMPs) and their synthetic variants are widely regarded as a potential source of future therapeutic agents against a broad range of pathogens. This is due to a remarkable set of advantageous properties, ranging from molecular simplicity that readily allows for time- and cost-efficient establishment of structure-activity relationships, to an essentially non-specific multitargeted mode of action, which significantly limits the capacity of pathogens to develop efficient resistance mechanisms. Nevertheless, difficult challenges need to be overcome as we move towards their eventual use in therapeutics, including improved bioavailability, toxicity and production costs. To address these issues, an increasingly rich variety of strategies for improving AMP properties are currently available for designing chemical mimics that reproduce the most critical biophysical characteristics of AMPs. In this chapter, I review the main strategies for the de novo design of AMP mimics that have generated systemically active lead compounds and showed promise for therapeutic development. Conceptually, the known designs can be distinguished on the basis of backbone rigidity. Thus, aft er a brief discussion of recent advances on representative approaches used to generate relatively stiffantimicrobial structures, this chapter focuses on the acyl-lysyl approach, which allows the design of structurally bendable molecules that none the less can selectively target a variety of microbial cells.