2. Academic Validation
  3. 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

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

  • Antiviral Res. 2024 Jul:227:105920. doi: 10.1016/j.antiviral.2024.105920.
Uyen Nguyen Phuong Le 1,  Yu-Jen Chang 2,  Chih-Hao Lu 3,  Yeh Chen 4,  Wen-Chi Su 5,  Shao-Ting Chao 6,  Lia A Baltina 7,  Svetlana F Petrova 7,  Sin-Rong Li 8,  Mien-Chie Hung 9,  Michael M C Lai 10,  Lidia A Baltina 11,  Cheng-Wen Lin 12
Affiliations

Affiliations

  • 1 Graduate Institute of Biological Science and Technology, China Medical University, Taichung, Taiwan; Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan.
  • 2 The Ph.D. Program of Biotechnology and Biomedical Industry, China Medical University, Taichung, Taiwan.
  • 3 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.
  • 4 Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, 402, Taiwan.
  • 5 Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
  • 6 Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan.
  • 7 Ufa Institute of Chemistry, Ufa Federal Research Center of the Russian Academy of Sciences, Russia.
  • 8 Department of Laboratory Medicine, China Medical University Hospital, Taichung, 404327, Taiwan.
  • 9 Research Center for Cancer Biology, China Medical University, Taichung, 404327, Taiwan; Center for Molecular Medicine, China Medical University Hospital, Taichung, 404327, Taiwan.
  • 10 Institute of Molecular Biology, Academia Sinica, Taipei, 115201, Taiwan.
  • 11 Ufa Institute of Chemistry, Ufa Federal Research Center of the Russian Academy of Sciences, Russia. Electronic address: baltina@anrb.ru.
  • 12 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.
PMID: 38821317 DOI: 10.1016/j.antiviral.2024.105920
Abstract

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.

Keywords

Glycyrrhizic acid derivative; Inhibitor; Mpro; Nirmatrelvir-resistant variant; Omicron; SARS-CoV-2.

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