Strategies in Translating the Therapeutic Potentials of Host Defense Peptides

Abstract

The golden era of antibiotics, heralded by the discovery of penicillin, has long been challenged by the emergence of antimicrobial resistance (AMR). Host defense peptides (HDPs), previously known as antimicrobial peptides, are emerging as a group of promising antimicrobial candidates for combatting AMR due to their rapid and unique antimicrobial action. Decades of research have advanced our understanding of the relationship between the physicochemical properties of HDPs and their underlying antimicrobial and non-antimicrobial functions, including immunomodulatory, anti-biofilm, and wound healing properties. However, the mission of translating novel HDP-derived molecules from bench to bedside has yet to be fully accomplished, primarily attributed to their intricate structure-activity relationship, toxicity, instability in host and microbial environment, lack of correlation between in vitro and in vivo efficacies, and dwindling interest from large pharmaceutical companies. Based on our previous experience and the expanding knowledge gleaned from the literature, this review aims to summarize the novel strategies that have been employed to enhance the antimicrobial efficacy, proteolytic stability, and cell selectivity, which are all crucial factors for bench-to-bedside translation of HDP-based treatment. Strategies such as residues substitution with natural and/or unnatural amino acids, hybridization, L-to-D heterochiral isomerization, C-and N-terminal modification, cyclization, incorporation with nanoparticles, and "smart design" using artificial intelligence technology, will be discussed. We also provide an overview of HDP-based treatment that are currently in the development pipeline.

Frog Skin-Derived Peptides Against Corynebacterium jeikeium: Correlation between Antibacterial and Cytotoxic Activities

“…Naturally-occurring antimicrobial peptides (AMPs) represent a valid alternative to traditional antibiotics, as they are active against a broad spectrum of microbes, from Gram-positive and Gram-negative bacteria to fungi and viruses [ 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. Furthermore, compared to conventional drugs, they have further biological functions, such as a wound-healing, antidiabetic, anti-inflammatory, and immune-modulatory activities [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. Amphibian skin secretion is considered a rich source of broad-spectrum AMPs, and over the years, numerous peptides have been isolated and classified into the corresponding families, such as esculentins, temporins, and bombinins H [ 32 , 33 ].…”

Figainin 1, a Novel Amphibian Skin Peptide with Antimicrobial and Antiproliferative Properties

“…However, several strategies have been proposed to increase selectivity, decreasing the hemolytic activity. Such strategies include residue substitution/incorporation with natural and/or unnatural amino acids, C- and N-terminal modification, cyclization, dimerization, l - to d- amino acid isomerization, incorporation with nanoformulations/nanoparticles, and the computer-aided design of AMPs using artificial intelligence technology to overcome the deleterious effects of some AMPs on host tissues [ 46 , 47 , 48 , 49 , 50 ]. An interesting example of the use of these technologies was the production of analogs of the hybrid antimicrobial peptide CA-MA, derived from two natural AMPs: residues 1 to 8 from Cecropin A (isolated from the hemolymph of Hyalophora cecropia , the giant silk moth) and residues 1 to 12 of Magainin 2 (isolated from the skin secretion of Xenopus laevis , the African clawed frog).…”

Antimicrobial Peptides Grafted onto a Plasma Polymer Interlayer Platform: Performance upon Extended Bacterial Challenge

“…AMPs have attracted considerable interest for the design of antibacterial coatings, [13][14][15][22][23][24] but some aspects, particularly longer-term performance, are still in need of further study, as is the question of whether some AMPs might be less effective due to conformational changes or accessibility after grafting with specific immobilization chemistries. Their potential use as covalently grafted protective coatings needs to be informed by considerations such as mechanism(s) of action and possible cytotoxicity.…”

“…[6][7][8][9] One class of molecules that has attracted considerable interest for the development of antimicrobial coatings is that of antimicrobial peptides (AMPs). [10][11][12][13][14][15] AMPs are part of the innate immune system and are involved in the first line of defence against bacterial invasion for all multicellular organisms. [10,11] AMPs have been isolated from a wide variety of animals, plants, bacteria, fungi and virus.…”