دورية أكاديمية
Glycyrrhizic acid conjugates with amino acid methyl esters target the main protease, exhibiting antiviral activity against wild-type and nirmatrelvir-resistant SARS-CoV-2 variants.
العنوان: | Glycyrrhizic acid conjugates with amino acid methyl esters target the main protease, exhibiting antiviral activity against wild-type and nirmatrelvir-resistant SARS-CoV-2 variants. |
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المؤلفون: | Le UNP; Graduate Institute of Biological Science and Technology, China Medical University, Taichung, Taiwan; Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan., Chang YJ; The Ph.D. Program of Biotechnology and Biomedical Industry, China Medical University, Taichung, Taiwan., Lu CH; The Ph.D. Program of Biotechnology and Biomedical Industry, China Medical University, Taichung, Taiwan; Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan; Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan., Chen Y; Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, 402, Taiwan., Su WC; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan., Chao ST; Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan., Baltina LA; Ufa Institute of Chemistry, Ufa Federal Research Center of the Russian Academy of Sciences, Russia., Petrova SF; Ufa Institute of Chemistry, Ufa Federal Research Center of the Russian Academy of Sciences, Russia., Li SR; Department of Laboratory Medicine, China Medical University Hospital, Taichung, 404327, Taiwan., Hung MC; Research Center for Cancer Biology, China Medical University, Taichung, 404327, Taiwan; Center for Molecular Medicine, China Medical University Hospital, Taichung, 404327, Taiwan., Lai MMC; Institute of Molecular Biology, Academia Sinica, Taipei, 115201, Taiwan., Baltina LA; Ufa Institute of Chemistry, Ufa Federal Research Center of the Russian Academy of Sciences, Russia. Electronic address: baltina@anrb.ru., Lin CW; Graduate Institute of Biological Science and Technology, China Medical University, Taichung, Taiwan; Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan; The Ph.D. Program of Biotechnology and Biomedical Industry, China Medical University, Taichung, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan. Electronic address: cwlin@mail.cmu.edu.tw. |
المصدر: | Antiviral research [Antiviral Res] 2024 Jul; Vol. 227, pp. 105920. Date of Electronic Publication: 2024 May 29. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: Elsevier Country of Publication: Netherlands NLM ID: 8109699 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-9096 (Electronic) Linking ISSN: 01663542 NLM ISO Abbreviation: Antiviral Res Subsets: MEDLINE |
أسماء مطبوعة: | Publication: Amsterdam : Elsevier Original Publication: [Amsterdam ; New York : Elsevier/North-Holland Biomedical Press, c1981- |
مواضيع طبية MeSH: | SARS-CoV-2*/drug effects , Antiviral Agents*/pharmacology , Antiviral Agents*/chemistry , Glycyrrhizic Acid*/pharmacology , Glycyrrhizic Acid*/chemistry , Coronavirus 3C Proteases*/antagonists & inhibitors , Coronavirus 3C Proteases*/metabolism , Drug Resistance, Viral*, Humans ; Esters/pharmacology ; Esters/chemistry ; Chlorocebus aethiops ; COVID-19 Drug Treatment ; Animals ; Vero Cells ; Molecular Docking Simulation ; Virus Replication/drug effects ; Protease Inhibitors/pharmacology ; Protease Inhibitors/chemistry ; COVID-19/virology ; Amino Acids/pharmacology ; Indoles/pharmacology ; Indoles/chemistry ; Mutation ; Lactams ; Leucine ; Nitriles ; Proline |
مستخلص: | COVID-19 pandemic is predominantly caused by SARS-CoV-2, with its main protease, Mpro, playing a pivotal role in viral replication and serving as a potential target for inhibiting different variants. In this study, potent Mpro inhibitors were identified from glycyrrhizic acid (GL) derivatives with amino acid methyl/ethyl esters. Out of the 17 derivatives semisynthesized, Compounds 2, 6, 9, and 15, with methionine methyl esters, D-tyrosine methyl esters, glutamic acid methyl esters, and methionines in the carbohydrate moiety, respectively, significantly inhibited wild-type SARS-CoV-2 Mpro-mediated proteolysis, with IC50 values ranging from 0.06 μM to 0.84 μM. They also demonstrated efficacy in inhibiting trans-cleavage by mutant Mpro variants (Mpro_P132H, Mpro_E166V, Mpro_P168A, Mpro_Q189I), with IC50 values ranging from 0.05 to 0.92 μM, surpassing nirmatrelvir (IC50: 1.17-152.9 μM). Molecular modeling revealed stronger interactions with Valine166 in the structural complex of Mpro_E166V with the compounds compared to nirmatrelvir. Moreover, these compounds efficiently inhibited the post-entry viral processes of wild-type SARS-CoV-2 single-round infectious particles (SRIPs), mitigating viral cytopathic effects and reducing replicon-driven GFP reporter signals, as well as in vitro infectivity of wild-type, Mpro_E166V, and Mpro_Q189I SRIPs, with EC50 values ranging from 0.02 to 0.53 μM. However, nirmatrelvir showed a significant decrease in inhibiting the replication of mutant SARS-CoV-2 SRIPs carrying Mpro_E166V (EC50: >20 μM) and Mpro_Q189I (EC50: 13.2 μM) compared to wild-type SRIPs (EC50: 0.06 μM). Overall, this study identifies four GL derivatives as promising lead compounds for developing treatments against various SARS-CoV-2 strains, including Omicron, and nirmatrelvir-resistant variants. Competing Interests: Declaration of competing interest Please find attached our Research Article “Glycyrrhizic acid conjugates with amino acid methyl esters target the main protease, exhibiting antiviral activity against wild-type and nirmatrelvir-resistant SARS-CoV-2 variants”, which we wish to submit for publication in Antiviral Research. All of the authors (Uyen Nguyen Phuong Le, Yu-Jen Chang, Chih-Hao Lu, Yeh Chen, Wen-Chi Su, Shao-Ting Chao, Lia A. Baltina, Svetlana F. Petrova, Sin-Rong Li, Mien-Chie Hung, Michael M. C. Lai, Lidia A. Baltina, Cheng-Wen Lin) declare no competing interests. (Copyright © 2024 Elsevier B.V. All rights reserved.) |
فهرسة مساهمة: | Keywords: Glycyrrhizic acid derivative; Inhibitor; Mpro; Nirmatrelvir-resistant variant; Omicron; SARS-CoV-2 |
المشرفين على المادة: | 0 (Antiviral Agents) 6FO62043WK (Glycyrrhizic Acid) EC 3.4.22.28 (Coronavirus 3C Proteases) 7R9A5P7H32 (nirmatrelvir) 0 (Esters) 0 (Protease Inhibitors) 0 (Amino Acids) 0 (Indoles) 0 (Lactams) GMW67QNF9C (Leucine) 0 (Nitriles) 9DLQ4CIU6V (Proline) |
SCR Organism: | SARS-CoV-2 variants |
تواريخ الأحداث: | Date Created: 20240531 Date Completed: 20240617 Latest Revision: 20240617 |
رمز التحديث: | 20240618 |
DOI: | 10.1016/j.antiviral.2024.105920 |
PMID: | 38821317 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1872-9096 |
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DOI: | 10.1016/j.antiviral.2024.105920 |