Host Defense Peptides as Templates for Antifungal Drug Development

Abstract

Current treatment for invasive fungal diseases is limited to three classes of antifungal drugs: azoles, polyenes, and echinocandins. The most recently introduced antifungal class, the echinocandins, was first approved nearly 30 years ago. The limited antifungal drug portfolio is rapidly losing its clinical utility due to the inexorable rise in the incidence of invasive fungal infections and the emergence of multidrug resistant (MDR) fungal pathogens. New antifungal therapeutic agents and novel approaches are desperately needed. Here, we detail attempts to exploit the antifungal and immunoregulatory properties of host defense peptides (HDPs) in the design and evaluation of new antifungal therapeutics and discuss historical limitations and recent advances in this quest.

Therapeutic Effect of an Antibody-Derived Peptide in a Galleria mellonella Model of Systemic Candidiasis

“…Moreover, the concept of host immunomodulation for treatment of fungal infections has gained attention in recent years, bringing the interest on immunomodulatory molecules, including antifungal peptides [41,[45][46][47]. Many host defense peptides have immunoregulatory properties that appear to be essential for antifungal responses of host cells and for antifungal efficacy in vivo [14,17,47,48].…”

“…Host defense peptides (HDPs) show a wide spectrum of biological activities and are emerging as a group of promising candidates for overcoming antimicrobial resistance due to their rapid and unique antimicrobial action [14][15][16]. Several reviews have described the antibacterial and antifungal properties of HDPs, their mechanisms of actions and their development for clinical applications [17][18][19][20][21][22][23].…”

Metamorphic Protein Folding Encodes Multiple Anti-Candida Mechanisms in XCL1

“…Fungi such as C. albicans cause severe infections [ 1 , 2 , 3 ], but currently available treatments have limited utility due to drug toxicity and the frequent emergence of drug resistance. Thus, new, less toxic antifungal drugs are needed, and antimicrobial proteins in the human immune system, such as chemokines, can inspire the design of such novel therapies [ 6 , 7 , 25 , 26 ]. Many human chemokines are known to be antifungal [ 13 , 14 , 21 ], including the chemokines XCL1 and CCL28 [ 18 ].…”

“…High incidence of drug toxicity and the emergence of resistance limit the utility of available antifungal drug classes [ 4 , 5 ]. Components of the innate immune system termed antimicrobial peptides, including certain chemokines, are currently under investigation as novel antifungal agents [ 6 , 7 ]. Detailed understanding of the relationship between protein structure and function can promote the optimal development of these peptides as therapeutics.…”

In Silico Predicted Antifungal Peptides: In Vitro and In Vivo Anti-Candida Activity

“…Recently, a new open-access database (DRAMP) containing over twenty thousand peptides, of which more than three thousand are characterized by antifungal activity, was developed [26]. To overcome the drawbacks of AMPs in relation to their efficacy, in vivo stability, toxicity, and expensive large-scale production, new strategies have been focusing on designing synthetic mimics and developing new delivery systems [15,[27][28][29][30]. Moreover, new strategies have been developed for molecular modifications and many peptides have been studied intensively, such as histatin-5 [29], lactoferricins [31], and anoplin [32].…”