Department of Chemistry, University of Alberta, Edmonton, AB T6G 2G2, Canada.
Department of Chemistry and Biochemistry, University of Texas at El Paso, El Paso, Texas 79968, United States.
J Am Chem Soc. 2021 Apr 14;143(14):5497-5507. doi: 10.1021/jacs.1c01186. Epub 2021 Mar 30.
Genetically encoded macrocyclic peptide libraries with unnatural pharmacophores are valuable sources for the discovery of ligands for many targets of interest. Traditionally, generation of such libraries employs "early stage" incorporation of unnatural building blocks into the chemically or translationally produced macrocycles. Here, we describe a divergent late-stage approach to such libraries starting from readily available starting material: genetically encoded libraries of peptides. A diketone linchpin 1,5-dichloropentane-2,4-dione converts peptide libraries displayed on phage to 1,3-diketone bearing macrocyclic peptides (DKMP): shelf-stable precursors for Knorr pyrazole synthesis. Ligation of diverse hydrazine derivatives onto DKMP libraries displayed on phage that carries silent DNA-barcodes yields macrocyclic libraries in which the amino acid sequence and the pharmacophore are encoded by DNA. Selection of this library against carbonic anhydrase enriched macrocycles with benzenesulfonamide pharmacophore and nanomolar . The methodology described in this manuscript can graft diverse pharmacophores into many existing genetically encoded phage libraries and significantly increase the value of such libraries in molecular discoveries.
具有非天然药效团的基因编码大环肽文库是发现许多感兴趣的靶标配体的宝贵资源。传统上，此类文库的生成采用“早期”将非天然构建块掺入化学或翻译产生的大环中。在这里，我们描述了一种从现成起始材料开始的发散的后期方法来制备此类文库：基于噬菌体展示的基因编码肽文库。二酮连接子 1,5-二氯戊烷-2,4-二酮将噬菌体展示的肽文库转化为含有 1,3-二酮的大环肽（DKMP）：Knorr 吡唑合成的稳定货架前体。将各种肼衍生物连接到噬菌体上展示的 DKMP 文库上，该文库带有沉默的 DNA 条码，可得到大环文库，其中氨基酸序列和药效团由 DNA 编码。该文库针对带有苯磺酰胺药效团和纳摩尔. 本文描述的方法可以将各种药效团嫁接到许多现有的基因编码噬菌体文库中，并显著提高此类文库在分子发现中的价值。
