Monreal I Abrrey, Contreras Erik M, Wayman Gary A, Aguilar Hector C, Saludes Jonel P
Immunology and Microbiology Department, Cornell University, Ithaca, NY 14850, USA.
Department of Chemistry, Washington State University, Pullman, WA 99164, USA.
Heliyon. 2020 Dec 24;6(12):e05780. doi: 10.1016/j.heliyon.2020.e05780. eCollection 2020 Dec.
The ability to access intracellular targets is of vital importance as the number of identified druggable intracellular targets increases every year. However, intracellular delivery poses a formidable barrier, as many potential therapeutics are impermeable to cell membranes, which hinders their practical application in drug development. Herein we present -designed unnatural cell penetrating peptide foldamers utilizing a 2,3-Didehydro-2-deoxyneuraminic acid (Neu2en) scaffold. Conveniently, this scaffold is amenable to standard Fmoc-based solid-phase peptide synthesis, with the advantages of tunable secondary structures and enhanced biostability. Flow cytometry and live-cell confocal microscopy studies showed that these Neu2en-based peptides, hereinafter termed SialoPen peptides, have significantly superior uptake in HeLa and primary neuronal hippocampal cells, outperforming the classical cell permeable peptides penetratin and HIV-TAT.
随着每年可成药细胞内靶点数量的增加，实现对细胞内靶点的作用能力至关重要。然而，细胞内递送构成了一个巨大的障碍，因为许多潜在的治疗药物无法穿透细胞膜，这阻碍了它们在药物开发中的实际应用。在此，我们展示了利用2,3-二脱氢-2-脱氧神经氨酸（Neu2en）支架设计的非天然细胞穿透肽折叠体。方便的是，这种支架适用于基于Fmoc的标准固相肽合成，具有可调节二级结构和增强生物稳定性的优点。流式细胞术和活细胞共聚焦显微镜研究表明，这些基于Neu2en的肽（以下称为SialoPen肽）在HeLa细胞和原代海马神经元细胞中的摄取显著优于经典的细胞穿透肽穿膜肽和HIV-TAT。
