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| 1 | Small molecule inhibitors reveal allosteric regulation of USP14 via steric blockade显示文摘The ubiquitin system is important for drug discovery,and the discovery of selective small-molecule inhibitors of deubiquitinating enzymes (DUBs) remains an active yet extremely challenging task. With a few exceptions,previously developed inhibitors have been found to bind the evolutionarily conserved catalytic centers of DUBs,resulting in poor selectivity. The small molecule IU1 was the first-ever specific inhibitor identified and exhibited surprisingly excellent selectivity for USP14 over other DUBs. However,the molecular mechanism for this selectivity was elusive. Herein,we report the high-resolution co-crystal structures of the catalytic domain of USP14 bound to IU1 and three IU1 derivatives. All the structures of these complexes indicate that IU1 and its analogs bind to a previously unknown steric binding site in USP14,thus blocking the access of the C-terminus of ubiquitin to the active site of USP14 and abrogating USP14 activity. Importantly,this steric site in USP14 is very unique,as suggested by structural alignments of USP14 with several known DUB X-ray structures. These results,in conjunction with biochemical characterization,Indicate a coherent steric blockade mechanism for U5P14 inhibition by compounds of the IU series. In light of the recent report of steric blockade of USP7 by FT671,this work suggests a potential generally applicable allosteric mechanism for the regulation of DUBs via steric blockade,as showcased by our discovery of IU1-248 which is 10-fold more potent than IU1. | Yiwei Wang Yuxuan Jiang Shan Ding Jiawang Li Ningjing Song Yujing Ren Danning Hong Cai Wu Bin Li Feng Wang Wei He Jiawei Wang Ziqing Mei | 2018 | Cell Research2018，28，12： | 15 |
| 2 | Chemical synthesis of Ub-AMC via ligation of peptide hydrazides显示文摘The C-terminal conjugate of ubiquitin with 7-amino-4-methylcoumarin (Ub-AMC) is an important probe for fluorescencebased analysis of deubiquitinating enzyme (DUB) activity. It is important to develop more efficient methods for the preparation of Ub-AMC because the currently available technology is still expensive for scaled-up production. In the present work we report an efficient strategy for total chemical synthesis of Ub-AMC through ligation of peptide hydrazides. Three peptide segments are assembled via N-to-C sequential ligation and the resulting product is converted to Ub-AMC via TCEP-mediated desulfurization. The synthetic Ub-AMC is shown to have expected biological functions | LIANG Jun FANG GeMin HUANG XiuLiang MEI ZiQing LI Juan TIAN ChangLin LIU Lei | 2013 | Science China Chemistry2013，56，9： | 2 |
| 3 | Discrimination of mitochondrial DNA 10400 locus by SNP-operated on/off Switch显示文摘Objective:To apply reformed AS-PCR, which combined phosphorothioate-modified primers with exo+ polymerase, in single nucle- otide polymorphism discrimination of mitochondrial DNA 10400 locus. Methods: We used the mtDNA 10400 locus to design unmodi- fied and 3′phosphorothioate-modified allele-specific primers for PCR, which was performed using polymerases with and without 3′exonuclease activities. The effects of these primers on primer-extension were evaluated by agarose gel electrophoresis. Results: The unmodified primers were extended by both exo- and exo+ polymerase irrespective of whether the primers were matched or mismatched with the templates. However, the 3′phosphorothioate-modified primers with a terminal mismatch triggered an' off- switch'of exo+ polymerase when compared to exo-polymerase. Conclusion: The'on/off'switch constituted by the combination of 3′phosphorothioate-modified primers with exo+ polymerase is a cost-effective, high-throughput and reliable method for SNP typing, which will be of enormous application in association studies by single nucleotide polymorphism screening. | Mei Hong Enben Su Ziqing Chen Xiaobing Ju Qi Chen Rong Zhou | 2008 | Journal of Nanjing Medical University2008，22，6： | 1 |
| 4 | A real-world study of immune checkpoint inhibitors in advanced triple-negative breast cancer显示文摘Background:Triple-negative breast cancer(TNBC)is the most aggressive type of breast cancer.Immune checkpoint inhibitors(ICIs)have been widely used to treat various tumors and have changed the landscape of tumor management,but the data from real-world studies of ICIs for TNBC treatment remain limited.The aim of this study was to evaluate the efficacy of ICIs in the treatment of patients with advanced TNBC in a real-world setting and to explore possible correlates.Methods:The clinical data of advanced TNBC patients who received ICI treatment in the Chinese People's Liberation Army(PLA)General Hospital were collected.Treatment responses,outcomes and adverse events(AEs)were assessed.Results:Eighty-one patients were included in the study.The confirmed objective response rate(ORR)was 32.1%,and the disease control rate(DCR)was 64.2%.The median progression-free survival(PFS)was 4.2 months,and the median overall survival(OS)was 11.0 months.PFS and OS were longer in patients who achieved clinical benefit from ICIs and shorter in patients who received later-line ICIs and higher levels of inflammation;specifically,patients with higher TILs had longer PFS.Overall AEs were tolerable.Conclusions:ICIs are effective in the treatment of advanced TNBC,and the adverse reactions are tolerable.A panel of biomarkers including LDH,ALP,and bNLR were identified to predict the efficacies of ICIs in TNBC treatment. | Zheng Zhang Yadi Zhang Chuanling Liu Jiakang Shao Yimeng Chen Yimin Zhu Li Zhang Boyu Qin Ziqing Kong Xixi Wang Yutong Wang Deqin Huang Liqun Liu Yuxin Zhou Ran Tao Zengjie Yang Mei Liu Weihong Zhao | 2023 | Cancer Innovation2023，2，3： | 0 |
| 5 | Semi-synthesis of Ubiquitin-propargylamide for identifying deubiquitinase targeting inhibitors显示文摘Ubiquitin-propargylamide(Ub-PA) is one of the most widely used activity-based probe to measure the activity of deubiquitinases(DUBs) and help validate DUBs targeting inhibitors. However, current synthetic route of Ub-PA is cumbersome. In this work, we report a novel semi-synthetic strategy to prepare Ub-PA in large-scale. Biochemical assays prove that semi-synthetic Ub-PA is an effective probe in identifying DUBs targeting inhibitors. | Xiaodan Tan Jingsi Bai Shan Ding Yujing Ren Danning Hong Ziqing Mei Yi-Ming Li | 2019 | Chinese Chemical Letters2019，30，3： | 0 |
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