Lee Myung-Ryul, Raman Namrata, Gellman Samuel H, Lynn David M, Palecek Sean P
Department of Chemical and Biological Engineering and ‡Department of Chemistry, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.
ACS Chem Biol. 2017 Dec 15;12(12):2975-2980. doi: 10.1021/acschembio.7b00843. Epub 2017 Nov 30.
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 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 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.
抗菌肽（AMPs）是颇具吸引力的抗真菌药物候选物，因为它们通过破坏细胞膜来杀死微生物，因此不太可能引发耐药性的产生。对真菌细胞和人类细胞的选择性较低以及在生理环境中的不稳定性限制了抗菌肽作为治疗药物的开发，但拟肽抗菌肽可以克服这些障碍，还能为抗菌肽的结构-功能关系提供有用的见解。在此，我们描述了以天然α-肽抗菌肽奥瑞因1.2为模板的抗真菌拟肽α/β-肽。这些α/β-奥瑞因类似物折叠成i → i + 4氢键连接的螺旋结构，其侧链功能排列方式与奥瑞因1.2几乎相同。通过改变电荷、疏水性、构象稳定性和α/β-氨基酸组成，我们设计出了具有活性和选择性的α/β-肽奥瑞因类似物，它们对机会致病菌白色念珠菌的最低抑菌浓度（MIC）比奥瑞因1.2低4倍，并且在MIC时引起的溶血率低于5%。这些α/β-奥瑞因类似物有望作为抗真菌治疗药物以及阐明抗菌肽活性和特异性机制的工具进行开发。
