Laboratoire de Chimie Bioorganique et Bioinorganique (LCBB) Institut de Chimie Moléculaire et des Matériaux d'Orsay (ICMMO) UMR 8182 CNRS Univ Paris Sud, Université Paris-Saclay , Orsay 91405 Cedex , France.
J Am Chem Soc. 2018 Jul 18;140(28):8756-8762. doi: 10.1021/jacs.8b04326. Epub 2018 Jul 3.
Artificial metalloenzymes are known to be promising tools for biocatalysis, but their recent compartmentalization has led to compatibly with cell components thus shedding light on possible therapeutic applications. We prepared and characterized artificial metalloenzymes based on the A adenosine receptor embedded in the cytoplasmic membranes of living human cells. The wild type receptor was chemically engineered into metalloenzymes by its association with strong antagonists that were covalently bound to copper(II) catalysts. The resulting cells enantioselectively catalyzed the abiotic Diels-Alder cycloaddition reaction of cyclopentadiene and azachalcone. The prospects of this strategy lie in the organ-confined in vivo preparation of receptor-based artificial metalloenzymes for the catalysis of reactions exogenous to the human metabolism. These could be used for the targeted synthesis of either drugs or deficient metabolites and for the activation of prodrugs, leading to therapeutic tools with unforeseen applications.
人工金属酶被认为是生物催化有前途的工具，但它们最近的区室化导致与细胞成分相容，从而为可能的治疗应用提供了线索。我们用人细胞的细胞质膜中嵌入的 A 腺苷受体为基础，制备和表征了人工金属酶。通过将野生型受体与共价结合到铜（II）催化剂上的强拮抗剂结合，将其化学工程化为金属酶。由此产生的细胞对非生物 Diels-Alder 环加成反应（环戊二烯和氮杂查尔酮）具有对映选择性催化作用。该策略的前景在于，在体内器官受限的情况下，基于受体的人工金属酶可用于催化人类新陈代谢以外的反应。这些可以用于靶向合成药物或缺乏的代谢物，并用于激活前药，从而为具有意想不到应用的治疗工具提供了可能性。
