Identification of highly selective covalent inhibitors by phage display.
Identification of highly selective covalent inhibitors by phage display.
复制标题
通过噬菌体显示鉴定高度选择性的共价抑制剂。
DOI：
10.1038/s41587-020-0733-7
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发表时间：
2021-04
影响因子：
46.9
通讯作者：
Bogyo M
中科院分区：
文献类型：
--
作者：
Chen S;Lovell S;Lee S;Fellner M;Mace PD;Bogyo M
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 inhibit 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.
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影响因子：
3.4
作者：
Cardote TA;Ciulli A
通讯作者：
Ciulli A
影响因子：
--
作者：
Albrow VE;Ponder EL;Fasci D;Békés M;Deu E;Salvesen GS;Bogyo M
通讯作者：
Bogyo M
影响因子：
56.9
作者：
MATTHEWS, DJ;WELLS, JA
通讯作者：
WELLS, JA
影响因子：
56.9
作者：
Cohen, MS;Zhang, C;Taunton, J
通讯作者：
Taunton, J
影响因子：
14.8
作者：
Heinis, Christian;Rutherford, Trevor;Winter, Greg
通讯作者：
Winter, Greg