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A Bioorthogonal Small Molecule Selective Polymeric “Clickase”
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2020-07-14 , DOI: 10.1021/jacs.0c06553
Junfeng Chen 1 , Ke Li 1 , Sarah E Bonson 1 , Steven C Zimmerman 1
Affiliation  

Synthetic polymer scaffolds may serve as gatekeepers preventing the adhesion of biomacromolecules. Herein, we use gating to develop a copper-containing single-chain nanoparticle (SCNP) catalyst as an artificial "clickase" that operates selectively on small molecules that are able to penetrate the polymeric shell. Whereas the analogous clickase with surface ammonium groups performs highly efficient copper(I)-catalyzed alkyne-azide cyclo-addition (CuAAC) reactions on both alkynylated proteins and small molecule substrates, the new SCNP clickase with polyethylene glycol (PEG) groups is only active on small molecules. Further, the new SCNP resists uptake by cells allowing extracellular click chemistry to be performed. We describe two proof of principle applications that illustrate the utility of the bioorthogonal activity. First, the SCNP catalyst is able to screen for ligands that bind proteins, including PROTAC-like molecules. Second, the non-membrane permeable SCNP can efficiently catalyze the click reaction extracellularly, thereby enabling in situ anticancer drug synthesis and screening without the catalyst perturbing intracellular functions.

中文翻译:


生物正交小分子选择性聚合“点击酶”



合成聚合物支架可以充当防止生物大分子粘附的守门人。在这里,我们使用门控开发了一种含铜单链纳米颗粒(SCNP)催化剂作为人工“点击酶”,选择性地作用于能够穿透聚合物壳的小分子。具有表面铵基团的类似点击酶可在炔基化蛋白质和小分子底物上进行高效的铜 (I) 催化的炔烃叠氮化物环加成 (CuAAC) 反应,而具有聚乙二醇 (PEG) 基团的新型 SCNP 点击酶仅具有活性在小分子上。此外,新的 SCNP 可以抵抗细胞的摄取,从而允许进行细胞外点击化学反应。我们描述了两个原理应用证明,说明了生物正交活动的实用性。首先,SCNP 催化剂能够筛选结合蛋白质的配体,包括类似 PROTAC 的分子。其次,非膜渗透性SCNP可以有效地催化细胞外的点击反应,从而能够在不干扰细胞内功能的情况下进行原位抗癌药物合成和筛选。
更新日期:2020-07-14
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