There is increasing interest in developing cationic host defense peptides (HDPs) and their synthetic derivatives as antimicrobial, immunomodulatory, and anti-biofilm agents. These activities are often evaluated without considering biologically relevant concentrations of salts or serum; furthermore certain HDPs have been shown to aggregatein vitro. Here we examined the effect of aggregation on the immunomodulatory activity of a synthetic innate defense regulator peptide, 1018 (VRLIVAVRIWRR-NH2). A variety of salts and solutes were screened to determine their influence on 1018 aggregation, revealing that this peptide “salts out” of solution in an anion-specific and concentration-dependent manner. Furthermore, the immunomodulatory activity of 1018 was found to be inhibited under aggregation-promoting conditions. A series of 1018 derivatives were synthesized with the goal of disrupting this self-assembly process. Indeed, some derivatives exhibited reduced aggregation while maintaining certain immunomodulatory functions, demonstrating that it is possible to engineer optimized synthetic HDPs to avoid unwanted peptide aggregation.

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聚集及其对合成先天防御防御肽的免疫调节活性的影响

对开发阳离子宿主防御肽（HDP）及其合成衍生物作为抗菌剂，免疫调节剂和抗生物膜剂的兴趣日益浓厚。通常在不考虑盐或血清生物学相关浓度的情况下评估这些活性。此外，已经表明某些HDP在体外聚集。在这里，我们检查了聚集对合成先天防御调节肽1018（VRLIVAVRIWRR-NH2）免疫调节活性的影响。筛选了各种盐和溶质，以确定它们对1018聚集的影响，表明该肽以阴离子特异性和浓度依赖性的方式从溶液中“盐析”。此外，发现1018的免疫调节活性在促进聚集的条件下被抑制。合成了一系列1018衍生物，目的是破坏这种自组装过程。实际上，某些衍生物在保持某些免疫调节功能的同时显示出减少的聚集，这表明可以设计优化的合成HDP以避免有害的肽聚集。