Etayash Hashem, Yip Fione, Hancock Robert E W
Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, 2259 Lower Mall Research Station, Vancouver, BC V6T 1Z4, Canada.
Pharmaceutics. 2023 May 1;15(5):1391. doi: 10.3390/pharmaceutics15051391.
The multifunctional properties of host defense peptides (HDPs) make them promising drug candidates to tackle bacterial infections and tissue inflammation. However, these peptides tend to aggregate and can harm host cells at high doses, potentially limiting their clinical use and applications. In this study, we explored the influences of both pegylation and glycosylation on the biocompatibility and biological properties of HDPs, particularly the innate defense regulator IDR1018. Two peptide conjugates were designed by attaching either polyethylene glycol (PEG6) or a glucose moiety to the peptide towards the N-terminus. Significantly, both derivatives reduced the aggregation, hemolysis, and cytotoxicity of the parent peptide by orders of magnitude. In addition, while the pegylated conjugate, PEG6-IDR1018, retained an excellent immunomodulatory profile, similar to that observed for IDR1018 itself, the glycosylated conjugate, Glc-IDR1018, significantly outperformed the parent peptide in inducing anti-inflammatory mediators, MCP1 and IL-1RA and in suppressing the level of lipopolysaccharide-induced proinflammatory cytokine IL-1β. Conversely, the conjugates led to a partial reduction in antimicrobial and antibiofilm activity. These findings underline the impacts of both pegylation and glycosylation on the biological properties of the HDP IDR1018 and indicate the potential of glycosylation to enhance the design of highly effective immunomodulatory peptides.
宿主防御肽（HDPs）的多功能特性使其成为治疗细菌感染和组织炎症的有前景的候选药物。然而，这些肽容易聚集，并且在高剂量时会损害宿主细胞，这可能会限制它们的临床应用。在本研究中，我们探讨了聚乙二醇化和糖基化对HDPs（特别是固有防御调节剂IDR1018）的生物相容性和生物学特性的影响。通过将聚乙二醇（PEG6）或葡萄糖部分连接到肽的N端设计了两种肽缀合物。值得注意的是，这两种衍生物都将母体肽的聚集、溶血和细胞毒性降低了几个数量级。此外，虽然聚乙二醇化缀合物PEG6-IDR1018保留了与IDR1018本身相似的优异免疫调节特性，但糖基化缀合物Glc-IDR1018在诱导抗炎介质MCP1和IL-1RA以及抑制脂多糖诱导的促炎细胞因子IL-1β水平方面明显优于母体肽。相反，这些缀合物导致抗菌和抗生物膜活性部分降低。这些发现强调了聚乙二醇化和糖基化对HDP IDR1018生物学特性的影响，并表明糖基化在增强高效免疫调节肽设计方面的潜力。
