DNA编码小分子文库的设计、合成与筛选
Design, synthesis and selection of DNA-encoded small-molecule libraries.
作者信息
Clark Matthew A, Acharya Raksha A, Arico-Muendel Christopher C, Belyanskaya Svetlana L, Benjamin Dennis R, Carlson Neil R, Centrella Paolo A, Chiu Cynthia H, Creaser Steffen P, Cuozzo John W, Davie Christopher P, Ding Yun, Franklin G Joseph, Franzen Kurt D, Gefter Malcolm L, Hale Steven P, Hansen Nils J V, Israel David I, Jiang Jinwei, Kavarana Malcolm J, Kelley Michael S, Kollmann Christopher S, Li Fan, Lind Kenneth, Mataruse Sibongile, Medeiros Patricia F, Messer Jeffrey A, Myers Paul, O'Keefe Heather, Oliff Matthew C, Rise Cecil E, Satz Alexander L, Skinner Steven R, Svendsen Jennifer L, Tang Lujia, van Vloten Kurt, Wagner Richard W, Yao Gang, Zhao Baoguang, Morgan Barry A
机构信息
Praecis Pharmaceuticals, Waltham, Massachusetts, USA
出版信息
Nat Chem Biol. 2009 Sep;5(9):647-54. doi: 10.1038/nchembio.211. Epub 2009 Aug 2.
Biochemical combinatorial techniques such as phage display, RNA display and oligonucleotide aptamers have proven to be reliable methods for generation of ligands to protein targets. Adapting these techniques to small synthetic molecules has been a long-sought goal. We report the synthesis and interrogation of an 800-million-member DNA-encoded library in which small molecules are covalently attached to an encoding oligonucleotide. The library was assembled by a combination of chemical and enzymatic synthesis, and interrogated by affinity selection. We describe methods for the selection and deconvolution of the chemical display library, and the discovery of inhibitors for two enzymes: Aurora A kinase and p38 MAP kinase.
生化组合技术，如噬菌体展示、RNA展示和寡核苷酸适配体，已被证明是生成针对蛋白质靶点的配体的可靠方法。将这些技术应用于小分子一直是人们长期追求的目标。我们报告了一个包含8亿个成员的DNA编码文库的合成与研究，其中小分子与编码寡核苷酸共价连接。该文库通过化学合成和酶促合成相结合的方式组装，并通过亲和选择进行研究。我们描述了化学展示文库的筛选和解卷积方法，以及两种酶——极光激酶A和p38丝裂原活化蛋白激酶抑制剂的发现。
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