Short Guanidinium‐Functionalized Poly(2‐oxazoline)s Displaying Potent Therapeutic Efficacy on Drug‐Resistant Fungal Infections

Abstract

New antifungals are urgently needed to combat invasive fungal infections, due to limited types of available antifungal drugs and frequently encountered side effects, as well as the quick emergence of drug‐resistance. We previously developed amine‐pendent poly(2‐oxazoline)s (POXs) as synthetic mimics of host defense peptides (HDPs) to have antibacterial properties, but with poor antifungal activity. Hereby, we report the finding of short guanidinium‐pendent POXs, inspired by cell‐penetrating peptides, as synthetic mimics of HDPs to display potent antifungal activity, superior mammalian cells versus fungi selectivity, and strong therapeutic efficacy in treating local and systemic fungal infections. Moreover, the unique antifungal mechanism of fungal cell membrane penetration and organelle disruption explains the insusceptibility of POXs to antifungal resistance. The easy synthesis and structural diversity of POXs imply their potential as a class of promising antifungal agents.

Advance and Designing Strategies in Polymeric Antifungal Agents Inspired by Membrane‐Active Peptides

“…We then designed and synthesized a series of guanidinium‐pendent poly(2‐oxazoline)s by cationic ring open polymerization of 2‐oxazoline monomers, followed by guanidinylation modification (Figure 9a) [25a] . The obtained poly(2‐oxazoline)s with different chain lengths ranging from 5–20 subunits showed narrow dispersity (Figure 9b).…”

Protected amine-functional initiators for the synthesis of α-amine homo- and heterotelechelic poly(2-ethyl-2-oxazoline)s

“…33,[33][34][35][36][37][38][39] For primary amine expression in the side chain, the preferred strategy encompasses the polymerization of tert-butyloxycarbonyl (BOC) protected amine-containing 2-oxazolines and their subsequent deprotection by trifluoroacetic acid (TFA). 29,[40][41][42] As for post polymerization modifications, orthogonally reactive monomers such as alkenes 43,44 and alkynes 45 can be selected to engage in click chemistries to attach the amine of choice. Display of secondary amines in the side chains can also be fashioned by hydrolysis of the oxazoline repeating units resulting in polyethyleneimine (PEI).…”

Guanylation Significantly Enhances the Antifungal Activity of Poly(α-lysine)

“…albicans and C. neoformans were greatly enhanced after guanidination . Liu et al reported that the antifungal activities of hyperbranched polylysines (HPLs) against Candida were increased by up to 32-fold when the amine groups were guanylated …”

“…33 Jiang et al found that the antifungal activities of poly(2-oxazoline)s against C. albicans and C. neoformans were greatly enhanced after guanidination. 34 Liu et al reported that the antifungal activities of hyperbranched polylysines (HPLs) against Candida were increased by up to 32-fold when the amine groups were guanylated. 35 In this paper, a series of α-PLns and guanylated α-PLn (α-PLn-Gxs, where x denotes the percentage of guanylation of amine groups) are successfully synthesized.…”