细胞质中小蛋白支架的递送可有效抑制 Ras 和 Myc。
Cytosolic Delivery of Small Protein Scaffolds Enables Efficient Inhibition of Ras and Myc.
机构信息
Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
Department Biochemistry and Molecular Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
出版信息
Mol Pharm. 2022 Apr 4;19(4):1104-1116. doi: 10.1021/acs.molpharmaceut.1c00798. Epub 2022 Feb 28.
The ability to deliver small protein scaffolds intracellularly could enable the targeting and inhibition of many therapeutic targets that are not currently amenable to inhibition with small-molecule drugs. Here, we report the engineering of small protein scaffolds with anionic polypeptides (ApPs) to promote electrostatic interactions with positively charged nonviral lipid-based delivery systems. Proteins fused with ApPs are either complexed with off-the-shelf cationic lipids or encapsulated within ionizable lipid nanoparticles for highly efficient cytosolic delivery (up to 90%). The delivery of protein inhibitors is used to inhibit two common proto-oncogenes, Ras and Myc, in two cancer cell lines. This report demonstrates the feasibility of combining minimally engineered small protein scaffolds with tractable nanocarriers to inhibit intracellular proteins that are generally considered "undruggable" with current small molecule drugs and biologics.
将小分子蛋白支架递送到细胞内的能力可以使靶向和抑制许多目前不能用小分子药物抑制的治疗靶点。在这里，我们报告了带有阴离子多肽（ApP）的小分子蛋白支架的工程设计，以促进与带正电荷的非病毒脂质递药系统的静电相互作用。与 ApP 融合的蛋白质要么与现成的阳离子脂质复合，要么封装在可离子化的脂质纳米颗粒中，以实现高效的细胞质递送（高达 90%）。蛋白质抑制剂的递送来抑制两种常见的原癌基因，Ras 和 Myc，在两种癌细胞系中。本报告证明了将最小工程化的小分子蛋白支架与易于处理的纳米载体相结合，以抑制通常被认为是“不可成药”的细胞内蛋白的可行性，这些蛋白目前可以用小分子药物和生物制剂来治疗。
Zotero 插件