Suppr超能文献

严重急性呼吸综合征冠状病毒3C样蛋白酶的底物特异性

The substrate specificity of SARS coronavirus 3C-like proteinase.

作者信息

Fan Keqiang, Ma Liang, Han Xiaofeng, Liang Huanhuan, Wei Ping, Liu Ying, Lai Luhua

机构信息

State Key Laboratory of Structural Chemistry of Stable and Unstable Species, College of Chemistry, Peking University, Beijing 100871, China.

出版信息

Biochem Biophys Res Commun. 2005 Apr 15;329(3):934-40. doi: 10.1016/j.bbrc.2005.02.061.

DOI:10.1016/j.bbrc.2005.02.061
PMID:15752746
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7092912/
Abstract

The 3C-like proteinase of severe acute respiratory syndrome coronavirus (SARS) has been proposed to be a key target for structural based drug design against SARS. We have designed and synthesized 34 peptide substrates and determined their hydrolysis activities. The conserved core sequence of the native cleavage site is optimized for high hydrolysis activity. Residues at position P4, P3, and P3' are critical for substrate recognition and binding, and increment of beta-sheet conformation tendency is also helpful. A comparative molecular field analysis (CoMFA) model was constructed. Based on the mutation data and CoMFA model, a multiply mutated octapeptide S24 was designed for higher activity. The experimentally determined hydrolysis activity of S24 is the highest in all designed substrates and is close to that predicted by CoMFA. These results offer helpful information for the research on the mechanism of substrate recognition of coronavirus 3C-like proteinase.

摘要

严重急性呼吸综合征冠状病毒（SARS）的3C样蛋白酶已被认为是基于结构的抗SARS药物设计的关键靶点。我们设计并合成了34种肽底物，并测定了它们的水解活性。对天然切割位点的保守核心序列进行了优化，以获得高水解活性。P4、P3和P3'位置的残基对于底物识别和结合至关重要，β-折叠构象倾向的增加也有帮助。构建了一个比较分子场分析（CoMFA）模型。基于突变数据和CoMFA模型，设计了一种具有更高活性的多重突变八肽S24。实验测定的S24水解活性在所有设计的底物中最高，且接近CoMFA预测值。这些结果为冠状病毒3C样蛋白酶底物识别机制的研究提供了有用信息。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21f0/7092912/fb4c28f32b94/gr1.jpg

相似文献

1
The substrate specificity of SARS coronavirus 3C-like proteinase.
Biochem Biophys Res Commun. 2005 Apr 15;329(3):934-40. doi: 10.1016/j.bbrc.2005.02.061.
2
The N-terminal octapeptide acts as a dimerization inhibitor of SARS coronavirus 3C-like proteinase.
Biochem Biophys Res Commun. 2006 Jan 20;339(3):865-72. doi: 10.1016/j.bbrc.2005.11.102. Epub 2005 Nov 28.
3
Biosynthesis, purification, and substrate specificity of severe acute respiratory syndrome coronavirus 3C-like proteinase.
J Biol Chem. 2004 Jan 16;279(3):1637-42. doi: 10.1074/jbc.M310875200. Epub 2003 Oct 15.
4
Virtual screening of novel noncovalent inhibitors for SARS-CoV 3C-like proteinase.
J Chem Inf Model. 2005 Jan-Feb;45(1):10-17. doi: 10.1021/ci049809b.
5
3C-like proteinase from SARS coronavirus catalyzes substrate hydrolysis by a general base mechanism.
Biochemistry. 2004 Apr 20;43(15):4568-74. doi: 10.1021/bi036022q.
6
A novel auto-cleavage assay for studying mutational effects on the active site of severe acute respiratory syndrome coronavirus 3C-like protease.
Biochem Biophys Res Commun. 2004 Nov 12;324(2):579-83. doi: 10.1016/j.bbrc.2004.09.088.
7
Quantitative Analysis of the Substrate Specificity of Human Rhinovirus 3C Protease and Exploration of Its Substrate Recognition Mechanisms.
ACS Chem Biol. 2020 Jan 17;15(1):63-73. doi: 10.1021/acschembio.9b00539. Epub 2019 Oct 29.
8
Mining SARS-CoV protease cleavage data using non-orthogonal decision trees: a novel method for decisive template selection.
Bioinformatics. 2005 Jun 1;21(11):2644-50. doi: 10.1093/bioinformatics/bti404. Epub 2005 Mar 29.
9
Study on substrate specificity at subsites for severe acute respiratory syndrome coronavirus 3CL protease.
Acta Biochim Biophys Sin (Shanghai). 2005 Dec;37(12):807-13. doi: 10.1111/j.1745-7270.2005.00114.x.
10
A computational analysis of SARS cysteine proteinase-octapeptide substrate interaction: implication for structure and active site binding mechanism.
BMC Bioinformatics. 2009 Jan 30;10 Suppl 1(Suppl 1):S48. doi: 10.1186/1471-2105-10-S1-S48.

引用本文的文献

1
Functionalization of a versatile fluorescent sensor for detecting protease activity and temporally gated opioid sensing.
RSC Chem Biol. 2025 Feb 18;6(4):555-562. doi: 10.1039/d4cb00276h. eCollection 2025 Apr 2.
2
An isothermal calorimetry assay for determining steady state kinetic and Ensitrelvir inhibition parameters for SARS-CoV-2 3CL-protease.
Sci Rep. 2024 Dec 31;14(1):32175. doi: 10.1038/s41598-024-81990-y.
3
Assay Development and Validation for Innovative Antiviral Development Targeting the N-Terminal Autoprocessing of SARS-CoV-2 Main Protease Precursors.
Viruses. 2024 Jul 29;16(8):1218. doi: 10.3390/v16081218.
4
Design, synthesis and biological evaluation of novel 3C-like protease inhibitors as lead compounds against SARS-CoV-2.
Future Med Chem. 2024;16(9):887-903. doi: 10.4155/fmc-2024-0015. Epub 2024 Apr 15.
5
Fragment-based Drug Discovery Strategy and its Application to the Design of SARS-CoV-2 Main Protease Inhibitor.
Curr Med Chem. 2024;31(38):6204-6226. doi: 10.2174/0109298673294251240229070740.
6
Comprehensive Understanding of the Kinetic Behaviors of Main Protease from SARS-CoV-2 and SARS-CoV: New Data and Comparison to Published Parameters.
Molecules. 2023 Jun 7;28(12):4605. doi: 10.3390/molecules28124605.
7
In Silico Design of New Dual Inhibitors of SARS-CoV-2 M through Ligand- and Structure-Based Methods.
Int J Mol Sci. 2023 May 6;24(9):8377. doi: 10.3390/ijms24098377.
8
Nirmatrelvir-resistant SARS-CoV-2 is efficiently transmitted in female Syrian hamsters and retains partial susceptibility to treatment.
Nat Commun. 2023 Apr 14;14(1):2124. doi: 10.1038/s41467-023-37773-6.
9
SARS-CoV-2 Main Protease Targets Host Selenoproteins and Glutathione Biosynthesis for Knockdown via Proteolysis, Potentially Disrupting the Thioredoxin and Glutaredoxin Redox Cycles.
Antioxidants (Basel). 2023 Feb 23;12(3):559. doi: 10.3390/antiox12030559.
10
Novel dithiocarbamates selectively inhibit 3CL protease of SARS-CoV-2 and other coronaviruses.
Eur J Med Chem. 2023 Mar 15;250:115186. doi: 10.1016/j.ejmech.2023.115186. Epub 2023 Feb 6.

本文引用的文献

1
Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins.
J Am Chem Soc. 1988 Aug 1;110(18):5959-67. doi: 10.1021/ja00226a005.
2
Virtual screening of novel noncovalent inhibitors for SARS-CoV 3C-like proteinase.
J Chem Inf Model. 2005 Jan-Feb;45(1):10-17. doi: 10.1021/ci049809b.
3
Characterization of SARS main protease and inhibitor assay using a fluorogenic substrate.
Biochem Biophys Res Commun. 2004 Jun 11;318(4):862-7. doi: 10.1016/j.bbrc.2004.04.098.
4
3C-like proteinase from SARS coronavirus catalyzes substrate hydrolysis by a general base mechanism.
Biochemistry. 2004 Apr 20;43(15):4568-74. doi: 10.1021/bi036022q.
5
Dissection study on the severe acute respiratory syndrome 3C-like protease reveals the critical role of the extra domain in dimerization of the enzyme: defining the extra domain as a new target for design of highly specific protease inhibitors.
J Biol Chem. 2004 Jun 4;279(23):24765-73. doi: 10.1074/jbc.M311744200. Epub 2004 Mar 22.
6
The crystal structures of severe acute respiratory syndrome virus main protease and its complex with an inhibitor.
Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13190-5. doi: 10.1073/pnas.1835675100. Epub 2003 Oct 29.
7
Prediction of proteinase cleavage sites in polyproteins of coronaviruses and its applications in analyzing SARS-CoV genomes.
FEBS Lett. 2003 Oct 23;553(3):451-6. doi: 10.1016/s0014-5793(03)01091-3.
8
Biosynthesis, purification, and substrate specificity of severe acute respiratory syndrome coronavirus 3C-like proteinase.
J Biol Chem. 2004 Jan 16;279(3):1637-42. doi: 10.1074/jbc.M310875200. Epub 2003 Oct 15.
9
Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs.
Science. 2003 Jun 13;300(5626):1763-7. doi: 10.1126/science.1085658. Epub 2003 May 13.
10
A novel coronavirus associated with severe acute respiratory syndrome.
N Engl J Med. 2003 May 15;348(20):1953-66. doi: 10.1056/NEJMoa030781. Epub 2003 Apr 10.

文献AI研究员

20分钟写一篇综述，助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型，支持多种主流文档格式。

立即体验