Improved potency and reduced toxicity of the antifungal peptoid AEC5 through submonomer modification

Abstract

As proteolytically stable peptidomimetics, peptoids could serve as antifungal agents to supplement a therapeutic field wrought with toxicity issues. We report the improvement of an antifungal peptoid, AEC5, through an iterative structure-activity relationship study. A sarcosine scan was used to first identify the most pharmacophorically important peptoid building blocks of AEC5, followed by sequential optimization of each building block. The optimized antifungal peptoid from this study, β−5, has improved potency towards Cryptococcus neoformans and decreased toxicity towards mammalian cells. For example, the selectivity ratio for C. neoformans over mammalian fibroblasts was improved from 8 for AEC5 to 37 for β−5.

Toward a clinical antifungal peptoid: Investigations into the therapeutic potential of AEC5

“…We note that these efforts have been concomitant with efforts to improve the potency and toxicity profile of AEC5 through structure activity relationship (SAR) studies . However, we sought to complete detailed analysis of AEC5 alongside SAR to contribute to the limited literature on antifungal peptoid mechanism of action and in vivo characteristics.…”

Recent advances in the development of anti-infective peptoids

“…14 Initial antifungal lead peptoids developed by the Bicker lab had SR values around 10 and were improved to >30 through iterative SAR studies. 57 Initial antiparasitic peptoids developed by the Cobb group had SR values ranging from 2.4 to 6. 62 Exploring expanded chemical space yielded peptoids with improved antiparasitic activity, but increased toxicity as well, limiting SR values to 1 or less.…”

“…6) with improved efficacy against C. neoformans and decreased toxicity against human hepatic cells. 57 Taken together, the most recent data on antifungal peptoids indicate that they could supplement the small collection of clinically used antifungal agents wrought with resistance and toxicity issues.…”

“…One particular phenomenon observed by our labs and others is the unique correlation between toxicity and side-chain length for cationic residues. 17,20,57 Cationic monomers with longer side chains (i.e., five or six methylenes) have increased toxicity compared to the monomer with four methylenes (NLys) due to increased C-H group hydrophobicity. Interestingly, as side chains are shortened to three or two methylenes, hydrophobicity and toxicity increase.…”

Peptoids with Antibiofilm Activity against the Gram Negative Obligate Anaerobe, Fusobacterium nucleatum

“…Whereas peptides have their side chain (R), attached to the α -carbon atom, the R group in peptoids is attached to the amide nitrogen, thus rendering peptoids stable to proteolytic degradation [ 10 ]. Peptoids have been shown to be very effective antimicrobials against a variety of different microbes [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. Several families of antimicrobial peptoids have been developed, including those based on repeating subunits [ 10 , 20 ].…”