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Molecular interaction of the antiviral compound CW?33 and its analogues with the NS2B?NS3 protease of the Japanese encephalitis virus.

ABSTRACT: In a previous study from our group, a novel compound, namely CW?33 (ethyl 2?(3',5'?dimethylanilino)??4?oxo?4,5?dihydrofuran?3?carboxylate) was identified that exhibited antiviral activity for Japanese encephalitis virus (JEV). The viral NS2B?NS3 serine protease serves an important role in cytoplasmic cleavage events that occur during viral polyprotein maturation. The inhibition of viral RNA and protein syntheses was responsible for the antiviral activities of the novel furanonaphthoquinone derivatives that were discovered for the prevention of JEV infection. Consequently, the present study examined the molecular docking simulation of JEV protease with compound CW?33 and its analogues, and developed quantitative structure?activity relationship (QSAR) models to assess the potential antiviral activities of these compounds with regard to JEV. Molecular docking simulation indicated the potential ligand?protein interactions associated with the antiviral activities of these compounds. According to the results of the QSAR models, the secondary amine group was an important moiety required for compound bioactivity, which enabled the formation of hydrogen bonding with the residue Glu155. Furthermore, the aromatic ring mapping of the phenyl moiety of each compound was predicted to form a ??cation interaction with residue Arg76, whereas the hydrophobic feature represented by the ethyl moiety exhibited hydrophobic contacts with residue Glu74. Finally, the hydrophobic substituents in the meta?position of the phenyl ring further contributed to the efficacy of the antiviral activity. These results unravel the structural characteristics that are required for binding of CW?33 to the JEV protease and can be used for potential therapeutic and drug development purposes for JEV.

SUBMITTER: Chen KC

PROVIDER: S-EPMC6443346 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Molecular interaction of the antiviral compound CW‑33 and its analogues with the NS2B‑NS3 protease of the Japanese encephalitis virus.

Chen Kuan-Chung KC Lin Yu-Fong YF Huang An-Cheng AC Gao Jing-Yang JY Lin Cheng-Wen CW Lien Jin-Cherng JC

International journal of molecular medicine 20190227 5

In a previous study from our group, a novel compound, namely CW‑33 (ethyl 2‑(3',5'‑dimethylanilino)‑4‑oxo‑4,5‑dihydrofuran‑3‑carboxylate) was identified that exhibited antiviral activity for Japanese encephalitis virus (JEV). The viral NS2B‑NS3 serine protease serves an important role in cytoplasmic cleavage events that occur during viral polyprotein maturation. The inhibition of viral RNA and protein syntheses was responsible for the antiviral activities of the novel furanonaphthoquinone deriv ...[more]

PMID: 30816489

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Project description:Japanese Encephalitis Virus (JEV) NS2B-NS3 is a protein complex composed of NS3 proteases and a NS2B cofactor. The N-terminal protease domain (180 residues) of NS3 (NS3(pro)) interacts directly with a central 40-amino acid hydrophilic domain of NS2B (NS2B(H)) to form an active serine protease. In this study, the recombinant NS2B(H)-NS3(pro) proteases were prepared in E. coli and used to compare the enzymatic activity between genotype I (GI) and III (GIII) NS2B-NS3 proteases. The GI NS2B(H)-NS3(pro) was able to cleave the sites at internal C, NS2A/NS2B, NS2B/NS3 and NS3/NS4A junctions that were identical to the sites proteolytically processed by GIII NS2B(H)-NS3(pro). Analysis of the enzymatic activity of recombinant NS2B(H)-NS3(pro) proteases using a model of fluorogenic peptide substrate revealed that the proteolytical processing activity of GIII NS2B(H)-NS3(pro) was significantly higher than that of GI NS2B(H)-NS3(pro). There were eight amino acid variations between GI and GIII NS2B(H)-NS3(pro), which may be responsible for the difference in enzymatic activities between GI and GIII proteases. Therefore, recombinant mutants were generated by exchanging NS2B(H) and NS3(pro) domains between GI and GIII NS2B(H)-NS3(pro) and subjected to protease activity analysis. Substitution of NS2B(H) significantly altered the protease activities, as compared to the parental NS2B(H)-NS3(pro), suggesting that NS2B(H) played an essential role in regulation of NS3(pro) protease activity. To further identify the amino acids responsible for the difference in protease activities, multiple substitution mutants including the individual and combined mutations at the variant residue 55 and 65 of NS2B(H) were generated and subjected to protease activity analysis. Replacement of NS2B-55 and NS2B-65 of GI to GIII significantly increased the enzymatic activity of GI NS2B(H)-NS3(pro) protease, whereas mutation of NS2B-55 and NS2B-65 of GIII to GI remarkably reduced the enzymatic activity of GIII NS2B(H)-NS3(pro) protease. Overall, these data demonstrated that NS2B-55 and NS2B-65 variations in hydrophilic domain of NS2B co-contributed to the difference in NS2B(H)-NS3(pro) protease activities between GI and GIII. These observations gain an insight into the role of NS2B in regulation of NS3 protease activities, which is useful for understanding the replication of JEV GI and GIII viruses.

Dataset Information

Molecular interaction of the antiviral compound CW?33 and its analogues with the NS2B?NS3 protease of the Japanese encephalitis virus.

Publications

Molecular interaction of the antiviral compound CW‑33 and its analogues with the NS2B‑NS3 protease of the Japanese encephalitis virus.

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