Construction of a Sequenceable Protein Mimetic Peptide Library with a True 3D Diversifiable Chemical Space

We present here a library of protein
mimetic bicyclic peptides.
These nanosized structures exhibit rigid backbones and spatially diversifiable
side chains. They present modular amino acids on all three linkages,
providing access to a true 3D diversifiable chemical space. These
peptides are synthesized through a Cu-catalyzed click reaction and
a Ru-catalyzed ring-closing metathesis reaction. Their bicyclic topology
can be reduced to a linear one, using Edman degradation and Pd-catalyzed
deallylation reactions. The linearization approaches allow de novo sequencing through mass spectrometry methods. We
demonstrate the function of a particular peptide that was identified
through a high throughput screening against the E363-R378 epitope on the intrinsically disordered c-Myc oncoprotein.
Intracellular delivery of this peptide could interfere with the c-Myc-mediated
transcription and inhibit proliferation in a human glioblastoma cell
line.

本研究报道了一类拟蛋白双环肽（protein mimetic bicyclic peptides）文库。该类纳米级结构具有刚性骨架与空间可调控修饰的侧链，其全部三个连接位点均搭载模块化氨基酸，可构建真正意义上的三维可修饰化学空间。该类肽通过铜催化点击反应（Cu-catalyzed click reaction）与钌催化闭环复分解反应（Ru-catalyzed ring-closing metathesis reaction）合成。借助艾德曼降解（Edman degradation）与钯催化脱烯丙基反应（Pd-catalyzed deallylation reactions），可将该双环拓扑结构转化为线性结构，该线性化策略可通过质谱法实现肽段的从头测序。本研究通过针对内在无序致癌蛋白c-Myc上E363-R378表位的高通量筛选（high throughput screening），获得了一款特定肽段并验证了其功能：将该肽段递送至细胞内后，可干扰c-Myc介导的转录过程，并在人类胶质母细胞瘤细胞系中抑制细胞增殖。