更新于：2024-11-01

CTSB x CTSL x TMPRSS2

更新于：2024-11-01

基本信息

关联

项与 CTSB x CTSL x TMPRSS2 相关的药物

212-148

靶点

CTSB x CTSL x TMPRSS2

作用机制

CTSB抑制剂 [+2]

在研机构

上海科技大学

原研机构

上海科技大学

在研适应症

新型冠状病毒感染

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 CTSB x CTSL x TMPRSS2 相关的临床结果

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100 项与 CTSB x CTSL x TMPRSS2 相关的转化医学

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0 项与 CTSB x CTSL x TMPRSS2 相关的专利（医药）

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项与 CTSB x CTSL x TMPRSS2 相关的文献（医药）

2024-04-01·Heliyon

Identification of receptors and factors associated with human coronaviruses in the oral cavity using single-cell RNA sequencing

Article

作者: Xia, Lixin ; Qin, Nianhong ; Lin, Weiming ; Chen, Xianxiong ; Liao, Mingfeng ; Wang, Xia ; Sha, Ou ; Chen, Qianming ; Zhang, Mingxia ; Gao, Feng

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) ravaged the world, and Coronavirus Disease 2019 (COVID-19) exhibited highly prevalent oral symptoms that had significantly impacted the lives of affected patients. However, the involvement of four human coronavirus (HCoVs), namely SARS-CoV-2, SARS-CoV, MERS-CoV, and HCoV-229E, in oral cavity infections remained poorly understood. We integrated single-cell RNA sequencing (scRNA-seq) data of seven human oral tissues through consistent normalization procedure, including minor salivary gland (MSG), parotid gland (PG), tongue, gingiva, buccal, periodontium and pulp. The Seurat, scDblFinder, Harmony, SingleR, Ucell and scCancer packages were comprehensively used for analysis. We identified specific cell clusters and generated expression profiles of SARS-CoV-2 and coronavirus-associated receptors and factors (SCARFs) in seven oral regions, providing direction for predicting the tropism of four HCoVs for oral tissues, as well as for dental clinical treatment. Based on our analysis, it appears that various SCARFs, including ACE2, ASGR1, KREMEN1, DPP4, ANPEP, CD209, CLEC4G/M, TMPRSS family proteins (including TMPRSS2, TMPRSS4, and TMPRSS11A), and FURIN, are expressed at low levels in the oral cavity. Conversely, BSG, CTSB, and CTSL exhibit enrichment in oral tissues. Our study also demonstrates widespread expression of restriction factors, particularly IFITM1-3 and LY6E, in oral cells. Additionally, some replication, assembly, and trafficking factors appear to exhibit broad oral tissues expression patterns. Overall, the oral cavity could potentially serve as a high-risk site for SARS-CoV-2 infection, while displaying a comparatively lower degree of susceptibility towards other HCoVs (including SARS-CoV, MERS-CoV and HCoV-229E). Specifically, MSG, tongue, and gingiva represent potential sites of vulnerability for four HCoVs infection, with the MSG exhibiting a particularly high susceptibility. However, the expression patterns of SCARFs in other oral sites demonstrate relatively intricate and may only be specifically associated with SARS-CoV-2 infection. Our study sheds light on the mechanisms of HCoVs infection in the oral cavity as well as gains insight into the characteristics and distribution of possible HCoVs target cells in oral tissues, providing potential therapeutic targets for HCoVs infection in the oral cavity.

2024-04-01·International Journal of Biological Macromolecules

Discovery of natural catechol derivatives as covalent SARS-CoV-2 3CLpro inhibitors

Article

作者: Lin, Guo-Qiang ; Liu, Donglan ; Wang, Feng ; Yuan, Jinwei ; Gao, Dingding ; Yuan, Shuai ; Cen, Yixin ; Zhao, Jingxian ; Tian, Ping ; Zhao, Jincun

The COVID-19 pandemic caused by SARS-CoV-2 continues to pose a threat to public health, and extensive research by scientists worldwide has also prompted the development of antiviral therapies. The 3C-like protease (3CL^pro) is critical for SARS-CoV-2 replication and acts as an effective target for drug development. To date, numerous of natural products have been reported to exhibit inhibitory effects on 3CL^pro, which encourages us to identify other novel inhibitors and elucidate their mechanism of action. In this study, we first screened an in-house compound library of 101 natural products using FRET assay, and found that oleuropein showed good inhibitory activity against SARS CoV-2 3CL^pro with an IC₅₀ value of 4.18 μM. Further studies revealed that the catechol core is essential for activity and can covalently bind to SARS-CoV-2 3CL^pro. Among other 45 catechol derivatives, wedelolactone, capsazepine and brazilin showed better SARS-CoV-2 3CL^pro inhibitory activities with IC₅₀ values of 1.35 μM, 1.95 μM and 1.18 μM, respectively. These catechol derivatives were verified to be irreversible covalent inhibitors by time-dependent experiments, enzymatic kinetic studies, dilution and dialysis assays. It also exhibited good selectivity towards different cysteine proteases (SARS-CoV-2 PL^pro, cathepsin B and cathepsin L). Subsequently, the binding affinity between brazilin and SARS-CoV-2 3CL^pro was determined by SPR assay with KD value of 0.80 μM. Molecular dynamic (MD) simulations study showed the binding mode of brazilin in the target protein. In particular, brazilin displayed good anti-SARS-CoV-2 activity in A549-hACE2-TMPRSS2 cells with EC₅₀ values of 7.85 ± 0.20 μM and 5.24 ± 0.21 μM for full time and post-infection treatments, respectively. This study provides a promising lead compound for the development of novel anti-SARS-CoV-2 drugs.

2024-03-19·Journal of Virology

Kidney organoids reveal redundancy in viral entry pathways during ACE2-dependent SARS-CoV-2 infection

Article

作者: Groenewegen, Ella ; Tan, Ker Sin ; Rudraraju, Rajeev ; Elliott, David A. ; Little, Melissa H. ; Neil, Jessica A. ; Karavendzas, Katerina ; Forbes, Thomas A. ; Vanslambrouck, Jessica M. ; Subbarao, Kanta ; Mah, Sophia ; Porrello, Enzo R.

ABSTRACTWith a high incidence of acute kidney injury among hospitalized COVID-19 patients, considerable attention has been focussed on whether SARS-CoV-2 specifically targets kidney cells to directly impact renal function, or whether renal damage is primarily an indirect outcome. To date, several studies have utilized kidney organoids to understand the pathogenesis of COVID-19, revealing the ability for SARS-CoV-2 to predominantly infect cells of the proximal tubule (PT), with reduced infectivity following administration of soluble ACE2. However, the immaturity of standard human kidney organoids represents a significant hurdle, leaving the preferred SARS-CoV-2 processing pathway, existence of alternate viral receptors, and the effect of common hypertensive medications on the expression of ACE2 in the context of SARS-CoV-2 exposure incompletely understood. Utilizing a novel kidney organoid model with enhanced PT maturity, genetic- and drug-mediated inhibition of viral entry and processing factors confirmed the requirement for ACE2 for SARS-CoV-2 entry but showed that the virus can utilize dual viral spike protein processing pathways downstream of ACE2 receptor binding. These include TMPRSS- and CTSL/CTSB-mediated non-endosomal and endocytic pathways, with TMPRSS10 likely playing a more significant role in the non-endosomal pathway in renal cells than TMPRSS2. Finally, treatment with the antihypertensive ACE inhibitor, lisinopril, showed negligible impact on receptor expression or susceptibility of renal cells to infection. This study represents the first in-depth characterization of viral entry in stem cell-derived human kidney organoids with enhanced PTs, providing deeper insight into the renal implications of the ongoing COVID-19 pandemic.IMPORTANCEUtilizing a human iPSC-derived kidney organoid model with improved proximal tubule (PT) maturity, we identified the mechanism of SARS-CoV-2 entry in renal cells, confirming ACE2 as the sole receptor and revealing redundancy in downstream cell surface TMPRSS- and endocytic Cathepsin-mediated pathways. In addition, these data address the implications of SARS-CoV-2 exposure in the setting of the commonly prescribed ACE-inhibitor, lisinopril, confirming its negligible impact on infection of kidney cells. Taken together, these results provide valuable insight into the mechanism of viral infection in the human kidney.

项与 CTSB x CTSL x TMPRSS2 相关的新闻（医药）

2023-12-02

·生物谷

Nature子刊｜孙蕾/杨海涛/姜标/陈新文/张磊砢合作开发基于宿主因子的抗新冠病毒广谱性疗法

现有的抗新冠病毒小分子药物主要靶向病毒主蛋白酶或RNA聚合酶，但由于新冠病毒为高突变的RNA病毒，存在产生耐药性的风险。因此，如何应对病毒的耐药性，仍是备受瞩目的关键科学问题。2023年11月21日，复旦大学生物医学研究院孙蕾研究员与上海科技大学免疫化学研究所杨海涛教授、姜标教授，广州实验室陈新文研究员、武汉病毒所张磊砢研究员等团队合作，于Nature系列期刊Nature Communications发表题为“Structure-based discovery of dual pathway inhibitors for SARS-CoV-2 entry”的基于宿主蛋白酶进行抗新冠病毒药物开发的最新研究成果，报道了多种靶向新冠病毒入侵过程中关键宿主蛋白酶TMPRSS2和CTSB/CTSL的抑制剂及其分子机制，并证实同时抑制以上蛋白酶可协同产生更有效的抗病毒作用。该研究为基于宿主蛋白酶的抗新冠病毒广谱性药物开发奠定了重要基础。新冠病毒在入侵过程中，既能通过质膜融合直接入侵(图1左，途径A)，也能在细胞内吞途径中完成膜融合(图1右，途径B)，释放病毒基因组。在两条入侵通路中，膜融合过程的发生分别需要依赖TMPRSS2和CTSB/CTSL对病毒刺突蛋白进行切割并激活其构象，从而介导后续的膜融合反应。由于宿主蛋白酶在新冠病毒的入侵过程中不可或缺的重要地位及其作为宿主蛋白相较于病毒蛋白保守性高，不易突变的特性，被认为是抗新冠病毒广谱性药物开发的理想靶点。图1. 新冠病毒入侵的两条途径及靶向其中宿主蛋白酶的抑制剂研究团队以TMPRSS2和CTSB/CTSL为研究对象，通过高通量筛选发现了多种具有靶向能力的强效抑制剂，并在细胞水平上展现出nM量级的抗病毒效果。研究团队进一步利用X-射线晶体学方法解析了上述多种抑制剂与其相应蛋白靶点的复合物结构，揭示了抑制剂靶向抑制的分子机制。值得一提的是，其中TMPRSS2与抑制剂的复合物结构首次揭示了TMPRSS2完整胞外域的结构信息。此外，研究团队发现联合使用靶向TMPRSS2和CTSB/CTSL的抑制剂分子nafamostat和K777，在抗病毒实验中具有更好的抗病毒效果(EC50=0.9 nM)，表现出“1+1>>2”的协同效应，表明同时抑制两条入侵通路是抗新冠药物开发的有效策略。在上述结构与抗病毒研究基础上，研究团队进一步设计了同时靶向TMPRSS2和CTSB/CTSL的“双活性”抑制剂212-148(图1)，其不仅在酶活试验中展现出双重抑制能力，同时也在细胞水平上展现出对不同新冠病毒突变株如Delta与Omicron感染的拮抗效果。上海科技大学免化所博士后王镐锋、广州实验室副研究员杨琪、上海科技大学免化所博士生刘小策、许孜立、硕士生邵茂林为论文的并列第一作者。上海科技大学杨海涛教授、复旦大学孙蕾研究员、上海科技大学姜标教授，广州实验室陈新文研究员、武汉病毒研究所张磊砢研究员为本文的共同通讯作者。注：文中插图源于 Nature Communications原文链接：https://doi.org/10.1038/s41467-023-42527-5本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！

临床研究