Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843, United States.
Department of Chemistry, Texas A&M University, College Station, Texas 77843, United States.
Bioconjug Chem. 2023 Oct 18;34(10):1861-1872. doi: 10.1021/acs.bioconjchem.3c00369. Epub 2023 Sep 29.
Cell-penetrating peptides (CPPs) are promising tools for the intracellular delivery of various biological payloads. However, the impact of payload conjugation on the cell-penetrating activity of CPPs is poorly understood. This study focused on dfTAT, a modified version of the HIV-TAT peptide with enhanced endosomal escape activity, to explore how different payloads affect its cell-penetrating activity. We systematically examined dfTAT conjugated with the SnoopTag/SnoopCatcher pair and found that while smaller payloads such as short peptides do not significantly impair dfTAT's cell delivery activity, larger payloads markedly reduce both its endocytic uptake and endosomal escape efficiency. Our results highlight the role of the payload size and bulk in limiting CPP-mediated delivery. While further research is needed to understand the molecular underpinnings of these effects, our findings pave the way for developing more effective CPP-based delivery systems.
细胞穿透肽 (CPPs) 是将各种生物有效载荷递送至细胞内的有前途的工具。然而，有效载荷缀合对接物穿透肽细胞穿透活性的影响知之甚少。本研究集中在 dfTAT 上，它是 HIV-TAT 肽的一种改良形式，具有增强的内体逃逸活性，旨在探讨不同有效载荷如何影响其细胞穿透活性。我们系统地研究了 dfTAT 与 SnoopTag/SnoopCatcher 对的缀合，发现虽然较小的有效载荷，如短肽，不会显著损害 dfTAT 的细胞递药活性，但较大的有效载荷则明显降低其内吞摄取和内体逃逸效率。我们的结果强调了有效载荷大小和体积在限制 CPP 介导的递药中的作用。虽然需要进一步研究来了解这些影响的分子基础，但我们的发现为开发更有效的基于 CPP 的递药系统铺平了道路。
