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Incorporation of β-Amino Acids Enhances the Antifungal Activity and Selectivity of the Helical Antimicrobial Peptide Aurein 1.2
ACS Chemical Biology ( IF 4 ) Pub Date : 2017-11-30 00:00:00 , DOI: 10.1021/acschembio.7b00843
Myung-Ryul Lee 1 , Namrata Raman 1 , Samuel H. Gellman 1 , David M. Lynn 1 , Sean P. Palecek 1
Affiliation  

Antimicrobial peptides (AMPs) are attractive antifungal drug candidates because they kill microbes via membrane disruption and are thus unlikely 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 analogs fold into ii + 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 analogs 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 analogs are promising candidates for development as antifungal therapeutics and as tools to elucidate mechanisms of AMP activity and specificity.

中文翻译:

β-氨基酸的掺入增强了螺旋抗菌肽Aurein 1.2的抗真菌活性和选择性

抗菌肽(AMPs)是有吸引力的抗真菌药物候选物,因为它们通过膜破坏杀死微生物,因此不太可能引起耐药性的发展。对真菌对人类细胞的低选择性以及在生理环境中的不稳定性限制了AMPs作为治疗剂的发展,但是拟肽AMPs可以克服这些障碍,并且还可以为AMP结构与功能之间的关系提供有用的见识。在这里,我们描述了天然α肽AMP aurein 1.2上模板化的抗真菌肽模拟物α/β肽。这些α/β-金黄色素类似物折叠成ii+ 4个H键螺旋,以与aurein 1.2几乎相同的方式呈现侧链功能阵列。通过改变电荷,疏水性,构象稳定性和α/β-氨基酸组织,我们设计了活性和选择性α/β-肽金黄色素类似物,它们对机会性病原体白色念珠菌的最低抑制浓度(MIC)低4倍。比aurein 1.2更高,并且在MIC处引起的溶血少于5%。这些α/β-金黄色素类似物是有望作为抗真菌治疗剂和阐明AMP活性和特异性机制的工具。
更新日期:2017-11-30
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