Glycyrrhizic Acid Derivatives Bearing Amino Acid Residues in the Carbohydrate Part as Dengue Virus E Protein Inhibitors: Synthesis and Antiviral Activity

Abstract

Dengue virus (DENV) is one of the most geographically distributed mosquito-borne flaviviruses, like Japanese encephalitis virus (JEV), and Zika virus (ZIKV). 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 <0.1 to 5.98 μM 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–activity 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.

Synthesis, Anti-Influenza H1N1 and Anti-Dengue Activity of A-Ring Modified Oleanonic Acid Polyamine Derivatives

“…With regard to the triterpenic derivatives, we have found very limited literature data on their suppressing activity against the Dengue virus. Thus, among semisynthetic derivatives, glycyrrhizic acid conjugates with isoleucine and aminodecanoic acid were found as potent anti-DENV-2 inhibitors, with range of IC 50 between 1.2–1.3 μM [ 51 ]; while valine or phenylalanine moieties showed, in vitro, the cytopathic effect 0.50 and 0.18 μM, respectively [ 52 ]. Taking into account the fact that the anti-Dengue antiviral activity of OA derivatives is still not known, we have evaluated compounds 5–8 and 23 against all dengue virus serotypes (DENV-1, -2, -3, -4) using the possibilities of cooperation in the framework of the joint project [ 53 ].…”

Exploring Host Factors of the Human Metabolism as Promising Targets for Dengue Treatment

“…Glycyrrhizic acid also suppresses autophagy in cells infected with DENV-2. This suppression is attributed to the inhibition of HMGB1 and leads to a reduction in DENV-2 replication [123,159]. Furthermore, glycyrrhizic acid derivatives exhibit antiviral activity against both DENV-1 and DENV-2, decreasing virus yield [160].…”