Reassessing the Host Defense Peptide Landscape

Abstract

Current research has demonstrated that small cationic amphipathic peptides have strong potential not only as antimicrobials, but also as antibiofilm agents, immune modulators, and anti-inflammatories. Although traditionally termed antimicrobial peptides (AMPs) these additional roles have prompted a shift in terminology to use the broader term host defense peptides (HDPs) to capture the multi-functional nature of these molecules. In this review, we critically examined the role of AMPs and HDPs in infectious diseases and inflammation. It is generally accepted that HDPs are multi-faceted mediators of a wide range of biological processes, with individual activities dependent on their polypeptide sequence. In this context, we explore the concept of chemical space as it applies to HDPs and hypothesize that the various functions and activities of this class of molecule exist on independent but overlapping activity landscapes. Finally, we outline several emerging functions and roles of HDPs and highlight how an improved understanding of these processes can potentially be leveraged to more fully realize the therapeutic promise of HDPs.

Keywords: antibiofilm peptide; antimicrobial peptide; chemical space; host defense peptide; peptide therapeutics.

Figure 1

The activity landscapes for HDPs are complex (represented as topographical maps) and encompass a variety of biophysical characteristics such as charge, hydrophobicity, amphipathicity, folding propensity, etc. When optimizing synthetic peptides by moving around the chemical space of an activity of interest (represented by the dashed line), it is necessary to consider how this sequence alteration may impact other peptide properties and/or activities. This could result in a convergence of activities within an HDP sequence (e.g., antimicrobial and immunomodulatory activities above) or a reduction in one activity type (e.g., cytotoxicity landscape above). Topographical maps were generated by Contour Map Creator (http://contourmapcreator.urgr8.ch/), and the maps shown are only illustrative and actually correspond to various locations near Vancouver, Canada.

Figure 2

Diversity of biological functions described for HDPs.