Dataset Information

Inhibitory effect of flavonoids against NS2B-NS3 protease of ZIKA virus and their structure activity relationship.

ABSTRACT:

Objectives

To determine the inhibitory activities of flavonoids against NS2B-NS3 protease of ZIKA virus (ZIKV NS2B-NS3^pro) expressed in Escherichia coli BL21 (DE3) and their structure activity relationship.

Results

ZIKV NS2B-NS3^pro was expressed in E. coli BL21(DE3) as a 35 kDa protein. It had a K _m of 26 µM with the fluorogenic peptide Dabcyl-KTSAVLQSGFRKME-Edan. The purified ZIKV NS2B-NS3^pro was used for inhibition and kinetic assays to determine the activities of 22 polyphenol compounds. These polyphenol compounds at 100 µM inhibited the activity of ZIKV NS2B-NS3^pro by 6.2-88%. Seven polyphenol compounds had IC₅₀ ranging from 22 ± 0.2 to 112 ± 5.5 µM. Myricetin showed a mixed type inhibitory pattern against ZIKV NS2B-NS3^pro protease. Its IC₅₀ value was 22 ± 0.2 µM with a K _i value of 8.9 ± 1.9 µM.

Conclusion

The chemical structure of a polyphenol compound and its inhibitory activity against ZIKV NS2B-NS3^pro can be explored to develop highly selective inhibitors against ZIKV NS2B-NS3^pro.

SUBMITTER: Lim HJ

PROVIDER: S-EPMC7088272 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Publications

Inhibitory effect of flavonoids against NS2B-NS3 protease of ZIKA virus and their structure activity relationship.

Lim Hee-Jung HJ Nguyen Thi Thanh Hanh TT Kim Nahyun M NM Park Jun-Seong JS Jang Tae-Su TS Kim Doman D

Biotechnology letters 20161124 3

<h4>Objectives</h4>To determine the inhibitory activities of flavonoids against NS2B-NS3 protease of ZIKA virus (ZIKV NS2B-NS3<sup>pro</sup>) expressed in Escherichia coli BL21 (DE3) and their structure activity relationship.<h4>Results</h4>ZIKV NS2B-NS3<sup>pro</sup> was expressed in E. coli BL21(DE3) as a 35 kDa protein. It had a K <sub>m</sub> of 26 µM with the fluorogenic peptide Dabcyl-KTSAVLQSGFRKME-Edan. The purified ZIKV NS2B-NS3<sup>pro</sup> was used for inhibition and kinetic assays t ...[more]

PMID: 27885509

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Project description:Zika virus (ZIKV) is a mosquito-borne flavivirus that causes severe neurological disorders, such as microcephaly in fetuses. Most recently, an outbreak of ZIKV started in Brazil in 2015. To date, no therapeutic agents have been approved to treat ZIKV infection in the clinic. Here, we screened a small molecule inhibitor that can inhibit the function of ZIKV non-structural protein 2B (NS2B)-NS3 protease (ZIKV NS2B-NS3 protease), thereby interfering with viral replication and spread. First, we identified the half maximal inhibitory concentration (IC50) of compound 3 (14.01 μM), 8 (6.85 μM), and 9 (14.2 μM) and confirmed that they are all non-competitive inhibitors. In addition, we have used the blind molecular docking method to simulate the inhibition area of three non-competitive inhibitors (compound 3, 8, and 9) with the ZIKV NS2B-NS3 protease. The results indicated that the four allosteric binding residues (Gln139, Trp148, Leu150, and Val220) could form hydrogen bonds or non-bonding interactions most frequently with the three compounds. The interaction might induce the reaction center conformation change of NS2B-NS3 protease to reduce catalyzed efficiency. The concentration of compounds required to reduce cell viability by 50% (CC50), and the concentration of compounds required to inhibit virus-induced cytopathic effect by 50% (EC50) of three potential compounds are >200 μM, 2.15 μM (compound 3), > 200 μM, 0.52 μM (compound 8) and 61.48 μM, 3.52 μM (compound 9), and Temoporfin are 61.05 μM, 2 μM, respectively. To select candidate compounds for further animal experiments, we analyzed the selectivity index (SI) of compound 3 (93.02), 8 (384.61), 9 (17.46), and Temoporfin (30.53, FDA-approved drug against cancer). Compound 8 has the highest SI value. Therefore, compound 8 was selected for verification in animal models. In vivo, compound 8 significantly delayed ZIKV-induced lethality and illness symptoms and decreased ZIKV-induced weight loss in a ZIKV-infected suckling mouse model. We conclude that compound 8 is worth further investigation for use as a potential future therapeutic agent against ZIKV infection.

Dataset Information

Inhibitory effect of flavonoids against NS2B-NS3 protease of ZIKA virus and their structure activity relationship.

Objectives

Results

Conclusion

Publications

Inhibitory effect of flavonoids against NS2B-NS3 protease of ZIKA virus and their structure activity relationship.

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