Jiang Ziqing, Kullberg Bart Jan, van der Lee Hein, Vasil Adriana I, Hale John D, Mant Colin T, Hancock Robert E W, Vasil Michael L, Netea Mihai G, Hodges Robert S
Department of Biochemistry & Molecular Genetics, School of Medicine, University of Colorado-Denver, Aurora, CO 80045, USA.
Chem Biol Drug Des. 2008 Dec;72(6):483-95. doi: 10.1111/j.1747-0285.2008.00728.x.
We utilized a series of analogs of D-V13K (a 26-residue amphipathic alpha-helical antimicrobial peptide, denoted D1) to compare and contrast the role of hydrophobicity on antifungal and antibacterial activity to the results obtained previously with Pseudomonas aeruginosa strains. Antifungal activity for zygomycota fungi decreased with increasing hydrophobicity (D-V13K/A12L/A20L/A23L, denoted D4, the most hydrophobic analog was sixfold less active than D1, the least hydrophobic analog). In contrast, antifungal activity for ascomycota fungi increased with increasing hydrophobicity (D4, the most hydrophobic analog was fivefold more active than D1). Hemolytic activity is dramatically affected by increasing hydrophobicity with peptide D4 being 286-fold more hemolytic than peptide D1. The therapeutic index for peptide D1 is 1569-fold and 62-fold better for zygomycota fungi and ascomycota fungi, respectively, compared with peptide D4. To reduce the hemolytic activity of peptide D4 and improve/maintain the antifungal activity of D4, we substituted another lysine residue in the center of the non-polar face (V16K) to generate D5 (D-V13K/V16K/A12L/A20L/A23L). This analog D5 decreased hemolytic activity by 13-fold, enhanced antifungal activity to zygomycota fungi by 16-fold and improved the therapeutic index by 201-fold compared with D4 and represents a unique approach to control specificity while maintaining high hydrophobicity in the two hydrophobic segments on the non-polar face of D5.
我们使用了一系列D-V13K（一种26个残基的两亲性α-螺旋抗菌肽，记为D1）的类似物，以比较疏水性在抗真菌和抗菌活性方面的作用，并与之前用铜绿假单胞菌菌株获得的结果进行对比。接合菌纲真菌的抗真菌活性随着疏水性增加而降低（D-V13K/A12L/A20L/A23L，记为D4，疏水性最强的类似物的活性比疏水性最弱的类似物D1低6倍）。相比之下，子囊菌纲真菌的抗真菌活性随着疏水性增加而增强（D4，疏水性最强的类似物的活性比D1高5倍）。溶血活性受疏水性增加的显著影响，肽D4的溶血活性比肽D1高286倍。与肽D4相比，肽D1对接合菌纲真菌和子囊菌纲真菌的治疗指数分别高1569倍和62倍。为了降低肽D4的溶血活性并提高/维持D4的抗真菌活性，我们在非极性面中心替换了另一个赖氨酸残基（V16K）以生成D5（D-V13K/V16K/A12L/A20L/A23L）。与D4相比，这种类似物D5的溶血活性降低了13倍，对接合菌纲真菌的抗真菌活性增强了16倍，治疗指数提高了201倍，代表了一种在保持D5非极性面两个疏水片段高疏水性的同时控制特异性的独特方法。
