检索结果-南通市图书馆

Identification of novel small-molecule inhibitors of SARS-CoV-2 by chemical genetics

ACTA PHARMACEUTICA SINICA B 2024年第9期14卷 4028-4044页

作者： Chan, Chris Chun-Yiu Guo, Qian Chan, Jasper Fuk-Woo Tang, Kaiming Cai, Jian-Piao Chik, Ka-Heng Chik, Kenn Ka-Heng Huang, Yixin Dai, Mei Qin, Bo Ong, Chon Phin Chu, Allen Wing-Ho Chan, Wan-Mui Ip, Jonathan Daniel Wen, Lei Tsang, Jessica Oi-Ling Wang, Tong-Yun Xie, Yubin Qin, Zhenzhi Cao, Jianli Ye, Zi-Wei Chu, Hin To, Kelvin Kai-Wang Ge, Xing-Yi Ni, Tao Jin, Dong-Yan Cui, Sheng Yuen, Kwok-Yung Yuan, Shuofeng Univ Hong Kong Li Ka Shing Fac Med Sch Clin Med State Key Lab Emerging Infect DisCarol Yu Ctr Inf Hong Kong 999077 Peoples R China Univ Hong Kong Shenzhen Hosp Dept Infect Dis & Microbiol Shenzhen 518000 Peoples R China Hong Kong Sci & Technol Pk Ctr Virol Vaccinol & Therapeut Hong Kong 999077 Peoples R China Hainan Med Univ Univ Hong Kong Joint Lab Trop Infe Academician Workstn Hainan Prov Haikou 571100 Peoples R China Univ Hong Kong Li Ka Shing Fac Med Sch Biomed Sci Pokfulam Hong Kong 999077 Peoples R China Chinese Acad Med Sci & Peking Union Med Coll NHC Key Lab Syst Biol Pathogens Inst Pathogen Biol Beijing 100730 Peoples R China Hunan Univ Coll Biol Hunan Prov Key Lab Med Virol Changsha 410082 Peoples R China

There are only eight approved small molecule antiviral drugs for treating COVID-19. Among them, four are nucleotide analogues (remdesivir, JT001, molnupiravir, and azvudine), while the other four are protease inhibitors (nirmatrelvir, ensitrelvir, leritrelvir, and simnotrelvir-ritonavir). Antiviral resistance, unfavourable drug-drug interaction, and toxicity have been reported in previous studies. Thus there is a dearth of new treatment options for SARS-CoV-2. In this work, a three-tier cell-based screening was employed to identify novel compounds with anti-SARS-CoV-2 activity. One compound, designated 172, demonstrated broad-spectrum antiviral activity against multiple human pathogenic coronaviruses and different SARS-CoV-2 variants of concern. Mechanistic studies validated by reverse genetics showed that compound 172 inhibits the 3-chymotrypsin-like protease (3CLpro) by binding to an allosteric site and reduces 3CLpro dimerization. A drug synergistic checkerboard assay demonstrated that compound 172 can achieve drug synergy with nirmatrelvir in vitro. . In vivo studies confirmed the antiviral activity of compound 172 in both Golden Syrian Hamsters and K18 humanized ACE2 mice. Overall, this study identified an alternative druggable site on the SARS-CoV-2 3CLpro, proposed a potential combination therapy with nirmatrelvir to reduce the risk of antiviral resistance and shed light on the development of allosteric protease inhibitors for treating a range of coronavirus diseases.

关键词： SARS-CoV-2 High throughput screening Broad-spectrum antiviral treatment 3CLpro inhibitor Allosteric-site inhibitor Animal models chemical genetics Reverse genetics CORONAVIRUS DIMERIZATION PNEUMONIA MECHANISM PROTEASES ACCURACY DIMER

来源：

维普期刊数据库评论

在线全文

维普期刊数据库

学校读者我要写书评

暂无评论

Identification of Methylosome Components as Negative Regulators of Plant Immunity Using chemical genetics

引用

Molecular Plant 2016年第12期9卷 1620-1633页

作者： Shuai Huang Aruna Balgi Yaping Pan Meng Li Xiaoran Zhang Lilin Du Ming Zhou Michel Roberge Xin Li Michael Smith Laboratories Department of Botany University of British Columbia Vancouver BC V6T 1Z4 Canada Department of Biochemistry and Molecular Biology University of British Columbia Vancouver BC V6T 1Z3 Canada Verna and Marrs McLean Department of Biochemistry and Molecular Biology Baylor College of Medicine Houston TX 77030 USA National Institute of Biological Sciences Beijing 102206 China

Nucleotide-binding leucine-rich repeat （NLR） proteins serve as immune receptors in both plants and animals. To identify components required for NLR-mediated immunity, we designed and carried out a chemical genetics screen to search for small molecules that can alter immune responses in Arabidopsis thaliana. From 13 600 compounds, we identified Ro 8-4304 that was able to specifically suppress the severe autoimmune phenotypes of chs3-2D （chilling sensitive 3, 2D）, including the arrested growth morphology and heightened PR （Pathogenesis Related） gene expression. Further, six Ro 8-4304 insensitive mutants were uncovered from the Ro 8-4304-insensitive mutant （rim） screen using a mutagenized chs3-2D popula- tion. Positional cloning revealed thatriml encodes an allele of AtlCIn （I, currents; CI, chloride; n, nucleotide）. Genetic and biochemical analysis demonstrated that AtlCIn is in the same protein complex with the meth- ylosome components small nuclear ribonucleoprotein D3b （SmD3b） and protein arginine methyltransferase 5 （PRMT5）, which are required for the biogenesis of small nuclear ribonucleoproteins （snRNPs） involved in mRNA splicing. Double mutant analysis revealed that SmD3b is also involved in the sensitivity to Ro 8-4304, and the prmt5-1 chs3-2D double mutant is lethal. Loss of At/C/n, SmD3b, or PRMT5 function results in enhanced disease resistance against the virulent oomycete pathogen Hyaloperonospora arabidopsidis Noco2, suggesting that mRNA splicing plays a previously unknown negative role in plant immunity. The successful implementation of a high-throughput chemical genetic screen and the identification of a small-molecule compound affecting plant immunity indicate that chemical genetics is a powerful tool to study whole-organism plant defense pathways.

关键词： chemical genetics small molecule screening plant immunity TNL autoimmunity methylosome

来源：

维普期刊数据库评论

在线全文

维普期刊数据库

学校读者我要写书评

暂无评论

Interplay of phytohormones and epigenetic regulation:A recipe for plant development and plasticity

引用

Journal of Integrative Plant Biology 2023年第2期65卷 381-398页

作者： Kai Jiang Hongwei Guo Jixian Zhai Institute of Plant and Food Science Key Laboratory of Molecular Design for Plant Cell Factory of Guangdong Higher Education InstitutesDepartment of BiologySchool of Life SciencesSouthern University of Science and Technology(SUSTech)Shenzhen 518055China

Both phytohormone signaling and epigenetic mechanisms have long been known to play crucial roles in plant development and plasticity in response to ambient ***,diverse signaling pathways mediated by phytohormones and epigenetic processes integrate multiple upstream signals to regulate various plant *** evidence indicates that phytohormones and epigenetic processes interact at multiple *** this review,we summarize the current knowledge of the interplay between phytohormones and epigenetic processes from the perspective of phytohormone *** also review chemical regulators used in epigenetic studies and propose strategies for developing novel regulators using multidisciplinary approaches.

关键词： chemical genetics epigenetics phytohormone plant growth and development plant growth regulator plasticity

来源：

维普期刊数据库

同方期刊数据库评论

在线全文

学校读者我要写书评

暂无评论

欢迎您,

建议与咨询留下您的常用邮箱和电话号码，以便我们向您反馈解决方案和替代方法

时间限定

文献类型

馆藏选择

核心期刊

语言

文献类型

帮助

文字说明：

检索规则说明：

检索范例：

分类表

所选分类

限定检索结果

文献类型

馆藏范围

日期分布

学科分类号

主题

机构

作者

语言

在线全文

在线全文

在线全文

请选择保存的检索档案：

请选择收藏分类：

通借通还

欢迎您,

建议与咨询 留下您的常用邮箱和电话号码，以便我们向您反馈解决方案和替代方法

时间限定

文献类型

馆藏选择

核心期刊

语言

文献类型

帮助

文字说明：

检索规则说明：

检索范例：

分类表

所选分类

限定检索结果

文献类型

馆藏范围

日期分布

学科分类号

主题

机构

作者

语言

在线全文

在线全文

在线全文

请选择保存的检索档案： 新增检索档案 确定 取消

请选择收藏分类： 新增自定义分类 确定 取消

通借通还

建议与咨询留下您的常用邮箱和电话号码，以便我们向您反馈解决方案和替代方法

请选择保存的检索档案：

请选择收藏分类：