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

Authors :
Yu-Feng Lin
Hsueh-Chou Lai
Chen-Sheng Lin
Ping-Yi Hung
Ju-Ying Kan
Shih-Wen Chiu
Chih-Hao Lu
Svetlana F. Petrova
Lidia Baltina
Cheng-Wen Lin
Source :
Viruses, Vol 16, Iss 12, p 1926 (2024)
Publication Year :
2024
Publisher :
MDPI AG, 2024.

Abstract

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.

Details

Language :
English
ISSN :
19994915
Volume :
16
Issue :
12
Database :
Directory of Open Access Journals
Journal :
Viruses
Publication Type :
Academic Journal
Accession number :
edsdoj.f27b730524404d728d48acc6b0fc993d
Document Type :
article
Full Text :
https://doi.org/10.3390/v16121926