Department of Biochemistry, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA.
Peptides. 2010 May;31(5):834-41. doi: 10.1016/j.peptides.2010.02.007. Epub 2010 Feb 16.
Targeting splicing machinery components is an underdeveloped strategy for cancer therapy. Uridine-rich small nuclear ribonucleoproteins (UsnRNPs) are essential spliceosome components that recognize splice sites in newly transcribed RNA. The major spliceosomal snRNPs are comprised of UsnRNA bound by a ring of Sm proteins. The survival of motor neuron (SMN) complex provides specificity for binding of Sm proteins to UsnRNAs. Three of the seven proteins that comprise the Sm core possess post-translationally modified C-terminal symmetric dimethylarginine (sDMA) residues which promote binding of these proteins to SMN. Here we describe a peptide inhibitor of sDMA that is capable of interfering with SMN/SmB interaction. The inhibitory peptide was attached to elastin-like polypeptide, a thermally responsive macromolecular carrier, in order to increase its stability and allow enhancement of its cellular uptake by thermal targeting. The fusion polypeptide inhibited the interaction of SMN/SmB, inhibited proliferation, and induced apoptosis in HeLa cells.
靶向剪接机制成分是癌症治疗中一个尚未充分开发的策略。富含尿嘧啶的小核核糖核蛋白（UsnRNPs）是识别新转录 RNA 中剪接位点所必需的剪接体成分。主要的剪接体 snRNPs 由与 Sm 蛋白形成环状的 UsnRNA 组成。运动神经元存活（SMN）复合物提供了 Sm 蛋白与 UsnRNA 结合的特异性。构成 Sm 核心的七种蛋白质中的三种具有翻译后修饰的 C 末端对称二甲基精氨酸（sDMA）残基，促进这些蛋白质与 SMN 的结合。在这里，我们描述了一种能够干扰 SMN/SmB 相互作用的 sDMA 肽抑制剂。该抑制肽被连接到弹性蛋白样多肽上，这是一种热响应的大分子载体，以增加其稳定性并通过热靶向增强其细胞摄取。融合多肽抑制了 SMN/SmB 的相互作用，抑制了 HeLa 细胞的增殖，并诱导了细胞凋亡。
