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Antimicrobial host defence peptides: functions and clinical potential

Abstract

Cationic host defence peptides (CHDP), also known as antimicrobial peptides, are naturally occurring peptides that can combat infections through their direct microbicidal properties and/or by influencing the host’s immune responses. The unique ability of CHDP to control infections as well as resolve harmful inflammation has generated interest in harnessing the properties of these peptides to develop new therapies for infectious diseases, chronic inflammatory disorders and wound healing. Various strategies have been used to design synthetic optimized peptides, with negligible toxicity. Here, we focus on the progress made in understanding the scope of functions of CHDP and the emerging potential clinical applications of CHDP-based therapies.

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Fig. 1: Structures of CHDP.
Fig. 2: Models of antibacterial mechanisms of CHDP.
Fig. 3: Summary of immunomodulatory mechanisms of CHDP.
Fig. 4: Common resistance mechanisms to CHDP in bacterial and fungal pathogens.

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Acknowledgements

N.M. is supported by the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council Canada for peptide research. M.A.A. is supported by the Australian Research Council. H.P.H. is supported by NWO-ZonMW and NWO-TTW Perspectief grants. D.J.D. is supported by the British Skin Foundation (026/s/17), Action Medical Research (GN2703) and the Chief Scientist Office (TCS/18/02). The authors also gratefully acknowledge Y. Gasper and M. Bleackley, La Trobe University, for their assistance with tables and figures.

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Correspondence to Neeloffer Mookherjee.

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Competing interests

N.M. is listed as an inventor on patents related to immunomodulatory aspects of host defence peptides and IDR peptides. M.A.A. is Chief Scientific Officer and Director of the start-up company Hexima, which has a cationic antimicrobial peptide in clinical trials for treatment of onychomycosis. H.P.H. owns stock in the start-up company Celestial Therapeutics Inc. and has patents on antimicrobial peptide therapeutics licensed to Zoetis. D.J.D. declares no conflict of interest.

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Glossary

Host defence peptides

Naturally occurring typically amphipathic cationic peptides that modulate host immune responses to control infection and regulate inflammation (commonly used as an alternative name for antimicrobial peptides to encompass all their functions).

Antimicrobial peptides

Naturally occurring cationic peptides, typically shorter than 50 amino acids in length, with the ability to kill microorganisms.

Defensins

A family of host defence peptides with a common β-sheet core stabilized with three or four disulfide bridges depending on the source.

Cathelicidin

A member of a family of host defence peptides named after the conserved cathelin-like domain in the propeptide precursor.

Histatins

A family of histidine-rich host defence peptides.

Peptidomimetics

Compounds that mimic a natural peptide and retain the biological function of the parent protein.

Innate defence regulator peptides

(IDR peptides). Small synthetic cationic peptides with immunomodulatory functions, derived from natural host defence peptides.

Cryptic peptides

Segments of secreted proteins identified by bioinformatics screening to potentially function as antimicrobial peptides.

Immune homeostasis

Balanced and tightly regulated immune response under physiologically normal conditions.

Immunomodulation

The process of activating, suppressing or altering the nature of immune function.

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Mookherjee, N., Anderson, M.A., Haagsman, H.P. et al. Antimicrobial host defence peptides: functions and clinical potential. Nat Rev Drug Discov 19, 311–332 (2020). https://doi.org/10.1038/s41573-019-0058-8

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