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Influence of hydrocarbon-stapling on membrane interactions of synthetic antimicrobial peptides
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2017-10-21 , DOI: 10.1016/j.bmc.2017.10.020
Tracy A. Stone , Gregory B. Cole , Huong Q. Nguyen , Simon Sharpe , Charles M. Deber

Cyclization has been recognized as a valuable technique for increasing the efficacy of small molecule and peptide therapeutics. Here we report the application of a hydrocarbon staple to a rationally-designed cationic antimicrobial peptide (CAP) that acquires increased membrane targeting and interaction vs. its linear counterpart. The previously-described CAP, 6K-F17 (KKKKKK-AAFAAWAAFAA-NH2) was used as the backbone for incorporation of an i to i + 4 helical hydrocarbon staple through olefin ring closing metathesis. Stapled versions of 6K-F17 showed an increase in non-selective membrane interaction, where the staple itself enhances the degree of membrane interaction and rate of cell death while maintaining high potency against bacterial membranes. However, the higher averaged hydrophobicity imparted by the staple also significantly increases toxicity to mammalian cells. This deleterious effect is countered through stepwise reduction of the stapled 6K-F17’s backbone hydrophobicity through polar amino acid substitutions. Circular dichroism assessment of secondary structure in various bacterial membrane mimetics reveals that a helical structure may improve – but is not an absolute requirement for – antimicrobial activity of 6K-F17. Further, phosphorus-31 static solid state NMR spectra revealed that both non-toxic stapled and linear peptides bind bacterial membranes in a similar manner that does not involve a detergent-like mechanism of lipid removal. The overall results suggest that the technique of hydrocarbon stapling can be readily applied to membrane-interactive CAPs to modulate how they interact and target biological membranes.



中文翻译:

碳氢键合对合成抗菌肽膜相互作用的影响

环化已被认为是提高小分子和肽治疗剂功效的有价值的技术。在这里,我们的烃订书钉的应用报告给合理设计阳离子抗微生物肽(CAP),其获取增加的膜定位和相互作用VS。它的线性对应物。先前描述的CAP 6K-F17(KKKKKK-AAFAAWAAFAA-NH 2)用作将i引入i  +  4的骨架螺旋烃通过烯烃闭环易位。6K-F17订书钉版本显示了非选择性膜相互作用的增加,其中订书钉本身增强了膜相互作用的程度和细胞死亡的速度,同时保持了对细菌膜的高效力。然而,钉书钉赋予的较高的平均疏水性也显着增加了对哺乳动物细胞的毒性。通过逐步减少极性氨基酸取代装订的6K-F17的主链疏水性,可以抵消这种有害作用。各种细菌膜模拟物中二级结构的圆二色性评估表明,螺旋结构可以改善6K-F17的抗菌活性,但并非绝对必要。进一步,磷31静态固态NMR光谱显示,无毒的固定肽和线性肽均以类似的方式结合细菌膜,而这种去除不涉及类似去污剂的脂质去除机理。总体结果表明,碳氢化合物装订技术可轻松应用于膜相互作用CAP,以调节它们如何相互作用和靶向生物膜。

更新日期:2017-10-21
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