拟肽
蛋白酶
化学
糜蛋白酶
部分
连接器
立体化学
配体(生物化学)
组合化学
生物化学
胰蛋白酶
酶
肽
受体
计算机科学
操作系统
作者
Deborah Grifagni,Elena Lenci,Alessia De De Santis,A Orsetti,Carlo Giorgio Barracchia,Filomena Tedesco,Raffaele Bellini Puglielli,F. Lucarelli,Angela Lauriola,Michael Assfalg,Francesca Cantini,V. Calderone,Daniele Guardavaccaro,Andrea Trabocchi,Mariapina D’Onofrio,Simone Ciofi‐Baffoni
标识
DOI:10.1021/acsmedchemlett.3c00498
摘要
We have applied a proteolysis targeting chimera (PROTAC) technology to obtain a peptidomimetic molecule able to trigger the degradation of SARS-CoV-2 3-chymotrypsin-like protease (3CLPro). The PROTAC molecule was designed by conjugating a GC-376 based dipeptidyl 3CLPro ligand to a pomalidomide moiety through a piperazine-piperidine linker. NMR and crystallographic data complemented with enzymatic and cellular studies showed that (i) the dipeptidyl moiety of PROTAC binds to the active site of the dimeric state of SARS-CoV-2 3CLPro forming a reversible covalent bond with the sulfur atom of catalytic Cys145, (ii) the linker and the pomalidomide cereblon-ligand of PROTAC protrude from the protein, displaying a high degree of flexibility and no interactions with other regions of the protein, and (iii) PROTAC reduces the protein levels of SARS-CoV-2 3CLPro in cultured cells. This study paves the way for the future applicability of peptidomimetic PROTACs to tackle 3CLPro-dependent viral infections.
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