Recently,a collaborative research study published in Science,led by Jun Wang,Xufang Deng,Eddy Arnold,and Francesc Xavier Ruiz1,identified a series of potent small molecule inhibitors that specifically target SARS-CoV-...Recently,a collaborative research study published in Science,led by Jun Wang,Xufang Deng,Eddy Arnold,and Francesc Xavier Ruiz1,identified a series of potent small molecule inhibitors that specifically target SARS-CoV-2 papain-like protease(PLpro).The study demonstrated nanomolar PLpro inhibitory potency with Ki values ranging from 13.2 to 88.2 nmol/L.By employing a structure-based drug design strategy,the researchers discovered an exceptionally promising compound,named Jun12682,that effectively targets both the newly discovered ubiquitin Val70(Val70Ub)-binding site and the known blocking loop(BL2)groove near the S4 subsite of PLpro.Furthermore,studies on the mechanism of action revealed that Jun12682 inhibits the deubiquitinating and deISGylating activities of PLpro,which are crucial for antagonizing the host’s innate immune response upon viral infection.Structural biology studies confirmed the“two-pronged”binding mode of Jun12682,aligning perfectly with their drug design rationale.Importantly,Jun12682 exhibited potent antiviral activity against SARS-CoV-2 and its variants,including nirmatrelvir-resistant mutants,in Caco-2 cells(EC50:0.44e2.02 mmol/L).It is noteworthy that its oral administration significantly improved survival rates and alleviated both lung virus loads and histopathological lesions in a lethal SARS-CoV-2 mouse model.In conclusion。展开更多
基金the Key Research and Development Program,the Ministry of Science and Technology of the People’s Republic of China(Grant No.2023YFC2606500)the Shandong Laboratory Program(SYS202205)The authors are also supported by the Korea Health Industry Development Institute(KHIDI)funded by the Ministry of Health&Welfare,the Republic of Korea(HI22C2067 to Meehyein Kim).Figure 1 was created using ChemDraw and Microsoft Office PowerPoint(PPT).
文摘Recently,a collaborative research study published in Science,led by Jun Wang,Xufang Deng,Eddy Arnold,and Francesc Xavier Ruiz1,identified a series of potent small molecule inhibitors that specifically target SARS-CoV-2 papain-like protease(PLpro).The study demonstrated nanomolar PLpro inhibitory potency with Ki values ranging from 13.2 to 88.2 nmol/L.By employing a structure-based drug design strategy,the researchers discovered an exceptionally promising compound,named Jun12682,that effectively targets both the newly discovered ubiquitin Val70(Val70Ub)-binding site and the known blocking loop(BL2)groove near the S4 subsite of PLpro.Furthermore,studies on the mechanism of action revealed that Jun12682 inhibits the deubiquitinating and deISGylating activities of PLpro,which are crucial for antagonizing the host’s innate immune response upon viral infection.Structural biology studies confirmed the“two-pronged”binding mode of Jun12682,aligning perfectly with their drug design rationale.Importantly,Jun12682 exhibited potent antiviral activity against SARS-CoV-2 and its variants,including nirmatrelvir-resistant mutants,in Caco-2 cells(EC50:0.44e2.02 mmol/L).It is noteworthy that its oral administration significantly improved survival rates and alleviated both lung virus loads and histopathological lesions in a lethal SARS-CoV-2 mouse model.In conclusion。
