当前位置:科学网首页 > 小柯机器人 >详情
噬菌体展示鉴定出高选择性共价抑制剂
作者:小柯机器人 发布时间:2020/11/17 14:04:17

近日,美国斯坦福大学医学院Matthew Bogyo及其团队通过噬菌体展示鉴定出高选择性共价抑制剂。相关论文于2020年11月16日在线发表在《自然—生物技术》杂志上。

研究人员报道了一种噬菌体展示方法,可以直接筛选通过共价键形成与蛋白质靶标结合的配体。这种方法利用反应性接头在噬菌体表面形成环肽,同时引入亲电子“弹头”与靶上的亲核试剂共价反应。使用这种方法,研究人员确定了具有纳摩尔浓度和超强特异性不可逆地抑制半胱氨酸蛋白酶和丝氨酸水解酶的环状肽。这种方法应该能够进行快速、无偏依的筛选,从而可鉴定出针对各种分子靶标的新型高选择性共价抑制剂。
 
据悉,共价结合大分子靶标的分子已广泛用作基于活性的探针和不可逆结合的药物。然而,共价键形成所需的亲电试剂的普遍反应性使得难以控制选择性。当前没有快速、无偏依的筛选方法从高度多样的候选分子库中鉴定出新型共价抑制剂。
 
附:英文原文

Title: Identification of highly selective covalent inhibitors by phage display

Author: Shiyu Chen, Scott Lovell, Sumin Lee, Matthias Fellner, Peter D. Mace, Matthew Bogyo

Issue&Volume: 2020-11-16

Abstract: Molecules that covalently bind macromolecular targets have found widespread applications as activity-based probes and as irreversibly binding drugs. However, the general reactivity of the electrophiles needed for covalent bond formation makes control of selectivity difficult. There is currently no rapid, unbiased screening method to identify new classes of covalent inhibitors from highly diverse pools of candidate molecules. Here we describe a phage display method to directly screen for ligands that bind to protein targets through covalent bond formation. This approach makes use of a reactive linker to form cyclic peptides on the phage surface while simultaneously introducing an electrophilic ‘warhead’ to covalently react with a nucleophile on the target. Using this approach, we identified cyclic peptides that irreversibly inhibited a cysteine protease and a serine hydrolase with nanomolar potency and exceptional specificity. This approach should enable rapid, unbiased screening to identify new classes of highly selective covalent inhibitors for diverse molecular targets.

DOI: 10.1038/s41587-020-0733-7

Source: https://www.nature.com/articles/s41587-020-0733-7

期刊信息

Nature Biotechnology:《自然—生物技术》,创刊于1996年。隶属于施普林格·自然出版集团,最新IF:31.864
官方网址:https://www.nature.com/nbt/
投稿链接:https://mts-nbt.nature.com/cgi-bin/main.plex