Development of NS2B-NS3 protease inhibitor that impairs Zika virus replication

doi:10.1016/j.virusres.2023.199092

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Title:	Development of NS2B-NS3 protease inhibitor that impairs Zika virus replication
Authors:	Lin, Wen-Wei Huang, Yi-Jung Wang, Yen-Tseng Lin, Yun-Syuan Mazibuko, Nonsikelelo Chen, Chien-Shu Cheng, Tian-Lu Chang, Chih-Shiang Leu, Yu-Ling Chen, Chiao-Yun Chuang, Chih-Hung
Contributors:	Kaohsiung Med Univ, Coll Med, Sch Post Baccalaureate Med, Dept Lab Med Kaohsiung Med Univ, Grad Inst Med, Coll Med Kaohsiung Med Univ, Drug Dev & Value Creat Res Ctr Kaohsiung Med Univ Hosp, Dept Med Res Kaohsiung Med Univ, Coll Med, Sch Post Baccalaureate Med, Dept Biochem Kaohsiung Med Univ, Dept Biomed Sci & Environm Biol China Med Univ, Sch Pharm China Med Univ, Drug Dev Ctr Chia Nan Univ Pharm & Sci, Dept Pharm Kaohsiung Med Univ Hosp, Dept Med Imaging Kaohsiung Med Univ, Coll Med, Sch Postbaccalaureate Med Kaohsiung Med Univ, Dept Med Lab Sci & Biotechnol Kaohsiung Med Univ, Dept Med Lab Sci & Biotechnol Kaohsiung Med Univ Hosp, Dept Med Imaging
Keywords:	Zika virus (ZIKV) ZIKV NS2B-NS3 protease Small molecule inhibitor Non-competitive
Date:	2023
Issue Date:	2024-12-25 11:04:51 (UTC+8)
Publisher:	ELSEVIER
Abstract:	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 com-pound 3 (14.01 mu M), 8 (6.85 mu M), and 9 (14.2 mu M) 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 mu M, 2.15 mu M (compound 3), > 200 mu M, 0.52 mu M (compound 8) and 61.48 mu M, 3.52 mu M (compound 9), and Temoporfin are 61.05 mu M, 2 mu M, 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.
Relation:	Virus Research, v.329, Article 199092
Appears in Collections:	[Offices] 456

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