Discovery of Potent Dengue Virus NS2B-NS3 Protease Inhibitors Among Glycyrrhizic Acid Conjugates with Amino Acids and Dipeptides Esters.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101509722 Publication Model: Electronic Cited Medium: Internet ISSN: 1999-4915 (Electronic) Linking ISSN: 19994915 NLM ISO Abbreviation: Viruses Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI

Glycyrrhizic Acid*/pharmacology ; Glycyrrhizic Acid*/chemistry ; Dengue Virus*/drug effects ; Dengue Virus*/enzymology ; Viral Nonstructural Proteins*/antagonists & inhibitors ; Viral Nonstructural Proteins*/metabolism ; Viral Nonstructural Proteins*/chemistry ; Molecular Docking Simulation* ; Antiviral Agents*/pharmacology ; Antiviral Agents*/chemistry ; Dipeptides*/pharmacology ; Dipeptides*/chemistry ; Esters*/chemistry ; Esters*/pharmacology ; Serine Endopeptidases*/metabolism ; Serine Endopeptidases*/chemistry ; Protease Inhibitors*/pharmacology ; Protease Inhibitors*/chemistry ; Amino Acids*/chemistry ; Amino Acids*/metabolism; Humans ; Binding Sites ; Drug Discovery ; Animals ; Viral Proteases

This study investigated a library of known and novel glycyrrhizic acid (GL) conjugates with amino acids and dipeptide esters, as inhibitors of the DENV NS2B-NS3 protease. We utilized docking algorithms to evaluate the interactions of these GL derivatives with key residues (His51, Asp75, Ser135, and Gly153) within 10 Å of the DENV-2 NS2B-NS3 protease binding pocket (PDB ID: 2FOM). It was found that compounds 11 and 17 exhibited unique binding patterns, forming hydrogen bonds with Asp75, Tyr150, and Gly153. Based on the molecular docking data, conjugates 11 with L-glutamic acid dimethyl ester, 17 with β-alanine ethyl ester, and 19 with aminoethantic acid methyl ester were further demonstrated as potent inhibitors of DENV-2 NS3 protease, with IC50 values below 1 μM, using NS3-mediated cleavage assay. Compound 11 was the most potent, with EC50 values of 0.034 μM for infectivity, 0.042 μM for virus yield, and a selective index over 2000, aligning with its strong NS3 protease inhibition. Compound 17 exhibited better NS3 protease inhibition than compound 19 but showed weaker effects on infectivity and virus yield. While all compounds strongly inhibited viral infectivity post-entry, compound 19 also blocked viral entry. This study provided valuable insights into the interactions between active GL derivatives and DENV-2 NS2B-NS3 protease, offering a comprehensive framework for identifying lead compounds for further drug optimization and design as NS2B-NS3 protease inhibitors against DENV.

Annu Rev Med. 2018 Jan 29;69:395-408. (PMID: 28846489)
Bioorg Khim. 2006 Nov-Dec;32(6):660-6. (PMID: 17180917)
Front Pharmacol. 2021 Jul 06;12:680674. (PMID: 34295250)
Nat Struct Mol Biol. 2006 Apr;13(4):372-3. (PMID: 16532006)
BMC Infect Dis. 2021 Oct 19;21(1):1078. (PMID: 34666692)
Science. 2015 Apr 17;348(6232):282-3. (PMID: 25883340)
Biochem Biophys Res Commun. 2017 Oct 28;492(4):631-642. (PMID: 28343993)
BMC Bioinformatics. 2011 Feb 15;12 Suppl 1:S33. (PMID: 21342564)
Eur J Med Chem. 2016 Mar 3;110:376-88. (PMID: 26866456)
Int J Infect Dis. 2020 Apr;93:268-276. (PMID: 32081774)
Bioorg Med Chem Lett. 2019 Oct 15;29(20):126645. (PMID: 31519375)
Med Res Rev. 2018 May;38(3):951-976. (PMID: 29350407)
Russ J Gen Chem. 2016;86(4):826-829. (PMID: 32288468)
Bioorg Med Chem Lett. 2015 Apr 15;25(8):1742-1746. (PMID: 25801933)
Pharmaceuticals (Basel). 2023 Apr 23;16(5):. (PMID: 37242424)
Antiviral Res. 2010 Mar;85(3):450-62. (PMID: 20060421)
Int J Mol Sci. 2024 Apr 16;25(8):. (PMID: 38673962)
Bioorg Med Chem Lett. 2024 Feb 1;99:129623. (PMID: 38242331)
Int J Mol Sci. 2022 Sep 07;23(18):. (PMID: 36142222)
Clin Microbiol Rev. 2016 Jul;29(3):695-747. (PMID: 27281742)
Curr Med Chem. 2020;27(30):4945-5036. (PMID: 30514185)
Int J Antimicrob Agents. 2020 Jun;55(6):105995. (PMID: 32335281)
PLoS One. 2007 May 09;2(5):e428. (PMID: 17502914)
PLoS Negl Trop Dis. 2021 Jul 22;15(7):e0009548. (PMID: 34292940)
Eur J Med Chem. 2015 Nov 13;105:263-73. (PMID: 26498572)
Antiviral Res. 2008 Jul;79(1):6-11. (PMID: 18423902)
Curr Drug Metab. 2020;21(6):436-465. (PMID: 32562521)
Viruses. 2022 Dec 21;15(1):. (PMID: 36680072)
Cell Res. 2016 Nov;26(11):1260-1263. (PMID: 27752039)
Russ J Bioorg Chem. 2017;43(4):456-462. (PMID: 32214781)
Virus Res. 2021 Mar;294:198290. (PMID: 33388394)
Antiviral Res. 2023 Aug;216:105653. (PMID: 37321487)
Curr Infect Dis Rep. 2010 May;12(3):157-64. (PMID: 21308524)
Curr Med Chem. 2020;27(36):6219-6243. (PMID: 31612817)
Mini Rev Med Chem. 2019;19(10):826-832. (PMID: 30659537)
Pharm Chem J. 2022;56(7):894-898. (PMID: 36268163)
Lancet. 2003 Jun 14;361(9374):2045-6. (PMID: 12814717)
Front Cell Infect Microbiol. 2023 Feb 14;13:1061937. (PMID: 36864886)
Molecules. 2022 Nov 07;27(21):. (PMID: 36364457)
J Am Chem Soc. 2019 May 1;141(17):6832-6836. (PMID: 31017399)
Pharmaceuticals (Basel). 2022 Sep 21;15(10):. (PMID: 36297280)
Eur J Med Chem. 2023 Aug 5;256:115416. (PMID: 37159959)
J Neurovirol. 2014 Dec;20(6):539-60. (PMID: 25287260)
Eur Rev Med Pharmacol Sci. 2020 Feb;24(4):2006-2011. (PMID: 32141569)
Antiviral Res. 2009 Jun;82(3):110-4. (PMID: 19428601)
Rev Med Virol. 2020 Mar;30(2):e2093. (PMID: 31833169)
J Med Chem. 2005 Feb 24;48(4):1256-9. (PMID: 15715493)
Antiviral Res. 2008 Nov;80(2):94-101. (PMID: 18674567)
Molecules. 2023 Nov 22;28(23):. (PMID: 38067449)
Chem Nat Compd. 2020;56(3):569-571. (PMID: 32836317)

Keywords: NS2B-NS3 protease; amino acids; antiviral activity; conjugates; dengue virus type 2; dipeptides; glycyrrhizic acid; synthesis

6FO62043WK (Glycyrrhizic Acid)
0 (Viral Nonstructural Proteins)
0 (Antiviral Agents)
EC 3.4.21.- (NS3 protease, dengue virus)
0 (Dipeptides)
0 (Esters)
EC 3.4.21.- (Serine Endopeptidases)
0 (Protease Inhibitors)
0 (Amino Acids)
0 (nonstructural protein 2B, Dengue virus)
0 (NS2B protein, flavivirus)
EC 3.4.- (Viral Proteases)

Date Created: 20250108 Date Completed: 20250108 Latest Revision: 20250108

20250129

PMC11680386

10.3390/v16121926

39772233