Department of Chemistry, University of Illinois, Urbana, Illinois 61801, United States.
J Am Chem Soc. 2020 Aug 12;142(32):13966-13973. doi: 10.1021/jacs.0c06553. Epub 2020 Jul 28.
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 cycloaddition (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 proteolysis targeting chimera (PROTAC)-like molecules. Second, the nonmembrane permeable SCNP can efficiently catalyze the click reaction extracellularly, thereby enabling in situ anticancer drug synthesis and screening without the catalyst perturbing intracellular functions.
合成聚合物支架可以作为“守门员”，防止生物大分子的黏附。在此，我们利用门控作用开发了一种含铜的单链纳米颗粒（SCNP）催化剂，作为一种人工“点击酶”，对能够穿透聚合物壳的小分子进行选择性操作。具有表面铵基团的类似点击酶能够在炔基化蛋白质和小分子底物上进行高效的铜（I）催化的叠氮-炔烃环加成（CuAAC）反应，而具有聚乙二醇（PEG）基团的新型 SCNP 点击酶仅对小分子具有活性。此外，新型 SCNP 抵抗细胞摄取，从而允许进行细胞外点击化学。我们描述了两个原理验证应用，说明了该生物正交活性的实用性。首先，SCNP 催化剂能够筛选与蛋白质结合的配体，包括蛋白水解靶向嵌合体（PROTAC）样分子。其次，非膜渗透的 SCNP 可以在细胞外有效地催化点击反应，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。
