School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, U.K.
Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, King Edwards VII Ave, Cardiff, CF10 3NB, U.K.
Chembiochem. 2022 Jun 20;23(12):e202200115. doi: 10.1002/cbic.202200115. Epub 2022 May 6.
Protein therapeutics offer exquisite selectivity in targeting cellular processes and behaviors, but are rarely used against non-cell surface targets due to their poor cellular uptake. While cell-penetrating peptides can be used to deliver recombinant proteins to the cytosol, it is generally difficult to selectively deliver active proteins to target cells. Here, we report a recombinantly produced, intracellular protein delivery and targeting platform that uses a photocaged intein to regulate the spatio-temporal activation of protein activity in selected cells upon irradiation with light. The platform was successfully demonstrated for two cytotoxic proteins to selectively kill cancer cells after photoactivation of intein splicing. This platform can generically be applied to any protein whose activity can be disrupted by a fused intein, allowing it to underpin a wide variety of future protein therapeutics.
蛋白质疗法在针对细胞过程和行为方面具有极高的选择性，但由于其细胞摄取能力差，很少用于针对非细胞表面的靶标。虽然细胞穿透肽可用于将重组蛋白递送至细胞质，但通常难以将活性蛋白选择性递送至靶细胞。在这里，我们报告了一种可重组产生的细胞内蛋白质递送和靶向平台，该平台使用光封闭的内含肽来调节在光照下照射时选定细胞中蛋白质活性的时空激活。该平台已成功用于两种细胞毒性蛋白，在光激活内含肽剪接后，可选择性杀死癌细胞。该平台可普遍应用于任何其活性可被融合内含肽破坏的蛋白质，使其能够为各种未来的蛋白质疗法提供基础。
