Incorporation of β-Amino Acids Enhances the Antifungal Activity and Selectivity of the Helical Antimicrobial Peptide Aurein 1.2

Abstract

Antimicrobial peptides (AMPs) are attractive antifungal drug candidates because they kill microbes via membrane disruption and are thus less likely to provoke development of resistance. Low selectivity for fungal vs. human cells and instability in physiological environments have limited the development of AMPs as therapeutics, but peptidomimetic AMPs can overcome these obstacles and also provide useful insight into AMP structure-function relationships. Here, we describe antifungal peptidomimetic α/β-peptides templated on the natural α-peptidic AMP aurein 1.2. These α/β-aurein analogues fold into i → i+4 H-bonded helices that present arrays of side chain functionality in a manner virtually identical to that of aurein 1.2. By varying charge, hydrophobicity, conformational stability, and α/β-amino acid organization we designed active and selective α/β-peptide aurein analogues that exhibit minimum inhibitory concentrations (MIC) against the opportunistic pathogen Candida albicans that are 4-fold lower than that of aurein 1.2 and elicit less than 5% hemolysis at the MIC. These α/β-aurein analogues are promising candidates for development as antifungal therapeutics and as tools to elucidate mechanisms of AMP activity and specificity.

Highly Efficient Stereoselective Synthesis of Βamino Acids by Asymmetric Method

“…Synthesis of β-amino acids are reported by using various chiral auxiliaries viz., pseudoephedrine 11 , hexahydrobenzoxazolidinone 2 , (4S)-4-benzyl-1,3-oxazolidin-2-one 13 . β-amino acids have numerous pharmacological properties as antidiabetic, antifungal, anthelmintic, and antimicrobial peptides [14][15][16] . Some of the important bioactive compounds containing β-amino acids are taurine, TGF-β, Amyloid-β-peptide, β-defensins, β-amino amides, Fascins, β-thromboglobulins, β-alanine, carnosine, β-Lactam.…”

Gramicidin‐S‐Inspired Cyclopeptidomimetics as Potent Membrane‐Active Bactericidal Agents with Therapeutic Potential

“…[9] As a result, the majority of clinical applicable AMPs are used or designed for topical applications only with very few exceptions aimed for systematic applications. [5] To overcome these limitations, many different strategies, including but not limited to structural/ sequence modification, [10][11][12][13] specific delivery system design, [14][15][16][17] "smart" AMPs [18][19][20] and de novo designed antimicrobial peptides/peptidomimetics [21][22][23][24][25][26][27] have been developed to efficiently use AMPs without being hindered by their side-effects. Among these strategies, modification or mimicry of naturally occurring peptides with natural amino acids or unnatural building blocks is an efficient pathway.…”

Small-Molecule Morphogenesis Modulators Enhance the Ability of 14-Helical β-Peptides To Prevent Candida albicans Biofilm Formation

“…These peptidomimetics can enhance AMP structural stability, including resistance to proteolytic cleavage, while retaining antimicrobial properties (21,23,29,30). Our research group has designed ␤-peptides and ␣/␤-peptides structurally templated on natural ␣-helical AMPs that exhibit toxicity toward planktonic C. albicans cells (32)(33)(34) and inhibit biofilm formation (24,35). Our prior results demonstrated that ␤-peptide hydrophobicity and helical stability are prime determinants of antifungal activity and hemolysis.…”

“…Our prior results demonstrated that ␤-peptide hydrophobicity and helical stability are prime determinants of antifungal activity and hemolysis. ␤-Peptide hydrophobicity directly correlated with antifungal activity and hemolysis, with a narrow concentration range at which the ␤-peptides effectively kill C. albicans cells without lysing red blood cells (32,33). Expanding this selective concentration range by reducing the hemolysis of hydrophobic ␤-peptides or increasing the activity of hydrophilic ␤-peptides would improve the therapeutic potential of antifungal ␤-peptides.…”