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In this study, a library of the known and novel Glycyrrhizic acid (GL) derivatives bearing amino acid residues or their methyl\/ethyl esters in the carbohydrate part were synthesized and studied as DENV inhibitors in vitro using the cytopathic effect (CPE), viral infectivity and virus yield assays with DENV1 and DENV-2 in Vero E6 and A549 cells. Among the GL conjugates tested, compound hits GL-D-ValOMe 3, GL-TyrOMe 6, GL-PheOEt 11, and GL-LysOMe 21 were discovered to have better antiviral activity than GL, with IC50 values ranging from &lt;0.1 to 5.98 \u03bcM on the in vitro infectivity of DENV1 and DENV2 in Vero E6 and A549 cells. Compound hits 3, 6, 11, and 21 had a concentration-dependent inhibition on the virus yield in Vero E6, in which GL-D-ValOMe 3 and GL-PheOEt 11 were the most active inhibitors of DENV2 yield. Meanwhile, the time-of-addition assay indicated that conjugates GL-D-ValOMe 3 and GL-PheOEt 11 exhibited a substantial decrease in the DENV2 attachment stage. Subsequently, chimeric single-round infectious particles (SRIPs) of DENV2 C-prM-E protein\/JEV replicon and DENV2 prM-E\/ZIKV replicon were utilized for the DENV envelope I protein-mediated attachment assay. GL conjugates 3 and 11 significantly reduced the attachment of chimeric DENV2 C-prM-E\/JEV and DENV2 prM-E\/ZIKV SRIPs onto Vero E6 cells in a concentration-dependent manner but did not impede the attachment of wild-type JEV CprME\/JEV and ZIKV prM-E\/ZIKV SRIPs, indicating the inhibition of Compounds 3 and 11 on DENV2 E-mediated attachment. Molecular docking data revealed that Compounds 3 and 11 have hydrophobic interactions within a hydrophobic pocket among the interfaces of Domains I, II, and the stem region of the DENV2 envelope (E) protein. These results displayed that Compounds 3 and 11 were the lead compounds targeting the DENV E protein. Altogether, our findings provide new insights into the structure\u2013activity relationship of GL derivatives conjugated with amino acid residues and can be the new fundamental basis for the search and development of novel flavivirus inhibitors based on natural compounds.<\/jats:p>","DOI":"10.3390\/ijms231810309","type":"journal-article","created":{"date-parts":[[2022,9,7]],"date-time":"2022-09-07T20:52:03Z","timestamp":1662583923000},"page":"10309","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Glycyrrhizic Acid Derivatives Bearing Amino Acid Residues in the Carbohydrate Part as Dengue Virus E Protein Inhibitors: Synthesis and Antiviral Activity"],"prefix":"10.3390","volume":"23","author":[{"given":"Mann-Jen","family":"Hour","sequence":"first","affiliation":[{"name":"School of Pharmacy, China Medical University, Taichung 40402, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yeh","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of New Drug Development, China Medical University, Taichung 40402, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chen-Sheng","family":"Lin","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Kuang Tien General Hospital, No. 117 Shatian Road, Shalu District, Taichung 43303, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6291-5260","authenticated-orcid":false,"given":"Lidia A.","family":"Baltina","sequence":"additional","affiliation":[{"name":"Ufa Institute of Chemistry, Ufa Federal Research Centre of RAS, 71 Prospect Oktyabrya, 450054 Ufa, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ju-Ying","family":"Kan","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Sciences, China Medical University, 91, Hsueh-Shin Road, Taichung 40402, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan-Ting","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Science and Biotechnology, China Medical University, 91 Hsueh-Shih Road, Taichung 40402, Taiwan"},{"name":"Department of Medical Laboratory Science and Biotechnology, Asia University, 500 Lioufeng Road, Wufeng, Taichung 41354, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan-Tung","family":"Kiu","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Science and Biotechnology, China Medical University, 91 Hsueh-Shih Road, Taichung 40402, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hsueh-Chou","family":"Lai","sequence":"additional","affiliation":[{"name":"School of Chinese Medicine, China Medical University, 91 Hsueh-Shih Road, Taichung 40402, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lia A.","family":"Baltina","sequence":"additional","affiliation":[{"name":"Ufa Institute of Chemistry, Ufa Federal Research Centre of RAS, 71 Prospect Oktyabrya, 450054 Ufa, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Svetlana F.","family":"Petrova","sequence":"additional","affiliation":[{"name":"Ufa Institute of Chemistry, Ufa Federal Research Centre of RAS, 71 Prospect Oktyabrya, 450054 Ufa, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0165-2652","authenticated-orcid":false,"given":"Cheng-Wen","family":"Lin","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Sciences, China Medical University, 91, Hsueh-Shin Road, Taichung 40402, Taiwan"},{"name":"Department of Medical Laboratory Science and Biotechnology, China Medical University, 91 Hsueh-Shih Road, Taichung 40402, Taiwan"},{"name":"Department of Medical Laboratory Science and Biotechnology, Asia University, 500 Lioufeng Road, Wufeng, Taichung 41354, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1007\/s13365-014-0285-z","article-title":"Flaviviruses, an expanding threat in public health: Focus on dengue, West Nile, and Japanese encephalitis virus","volume":"20","author":"Daep","year":"2014","journal-title":"J. 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