Potential of immunomodulatory host defense peptides as novel anti-infectives

Abstract

A fundamentally new strategy for the treatment of infectious disease is the modulation of host immune responses to enhance clearance of infectious agents and reduce tissue damage due to inflammation. Antimicrobial host defense peptides have been investigated for their potential as a new class of antimicrobial drugs. Recently their immunomodulatory activities have begun to be appreciated. Modulation of innate immunity by synthetic variants of host defense peptides, called innate defense regulators (IDRs), is protective without direct antimicrobial action. We discuss the potential and current limitations in exploiting the immunomodulatory activity of IDRs as a novel anti-infective pathway. IDRs show significant promise and current research is uncovering mechanistic information that will aid in the future development of IDRs for clinical use.

Figure 1

Design strategies for IDRs. Design and testing of IDRs are iterative processes. Initial candidate peptides are based on naturally occurring HDPs, designed using computational tools or randomly generated. These candidate peptides are tested in vitro and in vivo and computational analysis is used to select characteristics associated with function. New candidate peptides can then be designed using this structure–function relationship information and further testing reveals further information. Data from in vitro and in vivo testing also inform studies of the mechanism of action of IDRs and this information can feed back in to the bioinformatic and computational design approach. The structural diagram is LL-37 taken from the Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank.