Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
Sci Adv. 2020 Jun 19;6(25):eabb0310. doi: 10.1126/sciadv.abb0310. eCollection 2020 Jun.
Protein-based imaging agents and therapeutics are superior in structural and functional diversity compared to small molecules and are much easier to design or screen. Antibodies or antibody fragments can be easily raised against virtually any target. Despite these fundamental advantages, the power and impact of protein-based agents are substantially undermined, only acting on a limited number of extracellular targets because macrobiomolecules cannot spontaneously cross the cell membrane. Conventional protein delivery techniques fail to address this fundamental problem in that protein cargos are predominantly delivered inside cells via endocytosis, a remarkably effective cell defense mechanism developed by Mother Nature to prevent intact biomolecules from entering the cytoplasm. Here, we report a unique concept, noncovalent cholesterol tagging, enabling virtually any compact proteins to permeate through the cell membrane, completely bypassing endocytosis. This simple plug-and-play platform greatly expands the biological target space and has the potential to transform basic biology studies and drug discovery.
与小分子相比，基于蛋白质的成像剂和治疗剂在结构和功能多样性方面具有优势，而且设计或筛选也更加容易。几乎可以针对任何目标轻松制备抗体或抗体片段。尽管具有这些基本优势，但由于大分子不能自发穿过细胞膜，基于蛋白质的药物的作用范围和影响力受到了很大的限制，只能作用于少数细胞外靶点。传统的蛋白质递药技术未能解决这一根本问题，因为蛋白质药物主要通过内吞作用递送至细胞内，内吞作用是一种由大自然开发的非常有效的细胞防御机制，旨在防止完整的生物分子进入细胞质。在这里，我们报告了一种独特的概念，即非共价胆固醇标记，使几乎任何致密蛋白质都能够穿透细胞膜，完全绕过内吞作用。这个简单的即插即用平台极大地扩展了生物学靶标空间，具有改变基础生物学研究和药物发现的潜力。
