Very Short and Stable Lactoferricin-Derived Antimicrobial Peptides: Design Principles and Potential Uses

Abstract

CONSPECTUS:The alarming rate at which micro-organisms are developing resistance to conventional antibiotics represents one of the global challenges of our time. There is currently ample space in the antibacterial drug pipeline, and scientists are trying to find innovative and novel strategies to target the microbial enemies. Nature has remained a source of inspiration for most of the antibiotics developed and used, and the immune molecules produced by the innate defense systems, as a first line of defense, have been heralded as the next source of antibiotics. Most living organisms produce an arsenal of antimicrobial peptides (AMPs) to rapidly fend off intruding pathogens, and several different attempts have been made to transform this versatile group of compounds into the next generation of antibiotics. However, faced with the many hurdles of using peptides as drugs, the success of these defense molecules as therapeutics remains to be realized. AMPs derived from the proteolytic degradation of the innate defense protein lactoferrin have been shown to display several favorable antimicrobial properties. In an attempt to investigate the biological and pharmacological properties of these much shorter AMPs, the sequence dependence was investigated, and it was shown, through a series of truncation experiments, that these AMPs in fact can be prepared as tripeptides, with improved antimicrobial activity, via the incorporation of unnatural hydrophobic residues and terminal cappings. In this Account, we describe how this class of promising cationic tripeptides has been developed to specifically address the main challenges limiting the general use of AMPs. This has been made possible through the identification of the antibacterial pharmacophore and via the incorporation of a range of unnatural hydrophobic and cationic amino acids. Incorporation of these residues at selected positions has allowed us to extensively establish how these compounds interact with the major proteolytic enzymes trypsin and chymotrypsin and also the two major drug-binding plasma proteins serum albumin and α-1 glycoprotein. Several of the challenges associated with using AMPs relate to their size, susceptibility to rapid proteolytic degradation, and poor oral bioavailability. Our studies have addressed these issues in detail, and the results have allowed us to effectively design and prepare active and metabolically stable AMPs that have been evaluated in a range of functional settings. The optimized short AMPs display inhibitory activities against a plethora of micro-organisms at low micromolar concentrations, and they have been shown to target resistant strains of both bacteria and fungi alike with a very rapid mode of action. Our Account further describes how these compounds behave in in vivo experiments and highlights both the challenges and possibilities of the intriguing compounds. In several areas, they have been shown to exhibit comparable or superior activity to established antibacterial, antifungal, and antifouling commercial products. This il...

Cationic chitosan derivatives as potential antifungals: A review of structural optimization and applications

“…In recent years, a biomimetic strategy inspired by the structure of bacterial peptidoglycan has been very popular in the design and synthesis of chitosan-peptide conjugates (Svendsen, Grant, Rennison, Brimble, & Svenson, 2019;Takahashi, Caputo, Vemparala, & Kuroda, 2017). The newly obtained cationic peptide-polysaccharides with a peptidoglycan-mimetic structure, have been proven to display enhanced biocompatibility while still retaining the antimicrobial efficacy ( Fig.…”

Correlation between hemolytic activity, cytotoxicity and systemic in vivo toxicity of synthetic antimicrobial peptides

“…such as haemolytic activity is hampering the clinical development 4,6 . One of the main advantages of AMPs as potential candidate drugs is their pronounced selectivity for bacterial and fungal cells over eukaryotic cells 3,10 .…”

Lactoferrin-Derived Peptides as a Control Strategy against Skinborne Staphylococcal Biofilms

“…Moreover, the Lactoferrin chimera (LFchimera), a heterodimeric peptide containing LFmpin f (265-284), and a part of LFcinB f (17-30), was successfully tested for its antimicrobial and antibiofilm activities against multispecies biofilms derived from subgingival plaque of periodontitis; LFchimera antimicrobial and antibiofilm activities were stronger than chlorhexidine and minocycline hydrochloride, usually used in oral care products [55]. Further evidence concerning the antibiofilm activities were obtained against other microorganisms for human lactoferrin derived peptides, such as LFcinH, f (1-11), and its derivatives chemically modified [56][57][58]; lactoferrin, indeed, is widely represented in human and animals, where it exhibits a wide spectrum of biological functions [34]; the amino acid sequences of human lactoferrin and BLF share 69% similarity.…”

“…Thus, in accordance with the results of our previous works the evidence reported in this work highlights the promising potential of BLF-derived peptides that, if further investigated, could be exploited to obtain peptidomimetics with improved antibiofilm activity. Recently, in the attempt to overcome problems limiting the general use of AMPs, Svendsen et al [58] designed LFcinH derived tripeptides with improved drug-like properties; in particular, authors identified the "minimal antibacterial motif" and introduced synthetic amino acid residues improving their antimicrobial and antibiofilm activity. The beneficial effects of this approach also included improved bioavailability, metabolic stability, and rapid mode of action, making them suitable for several applications (i.e., topical use; [58]).…”