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Title: Structures of Zika virus NS2B-NS3 protease in complex with peptidomimetic inhibitors
Authors: Phoo, Wint Wint
Zhang, Zhenzhen
Wirawan, Melissa
Chew, Edwin Jun Chen
Chew, Alvin Bing Liang
Kouretova, Jenny
Steinmetzer, Torsten
Luo, Dahai
Keywords: Science::Medicine
NS3 Protease
Zika Virus
Issue Date: 2018
Source: Phoo, W. W., Zhang, Z., Wirawan, M., Chew, E. J. C., Chew, A. B. L., Kouretova, J., . . . Luo, D. (2018). Structures of Zika virus NS2B-NS3 protease in complex with peptidomimetic inhibitors. Antiviral Research, 160, 17-24. doi:10.1016/j.antiviral.2018.10.006
Series/Report no.: Antiviral Research
Abstract: Zika virus NS2B-NS3 protease plays an essential role in viral replication by processing the viral polyprotein into individual proteins. The viral protease is therefore considered as an ideal antiviral drug target. To facilitate the development of protease inhibitors, we report three high-resolution co-crystal structures of bZiPro with peptidomimetic inhibitors composed of a P1-P4 segment and different P1′ residues. Compounds 1 and 2 possess small P1′ groups that are split off by bZiPro, which could be detected by mass spectrometry. On the other hand, the more potent compound 3 contains a bulky P1′ benzylamide structure that is resistant to cleavage by bZiPro, demonstrating that presence of an uncleavable C-terminal cap contributes to a slightly improved inhibitory potency. The N-terminal phenylacetyl residue occupies a position above the P1 side chain and therefore stabilizes a horseshoe-like backbone conformation of the bound inhibitors. The P4 moieties show unique intra- and intermolecular interactions. Our work reports the detailed binding mode interactions of substrate-analogue inhibitors within the S4-S1′ pockets and explains the preference of bZiPro for basic P1-P3 residues. These new structures of protease-inhibitor complexes will guide the design of more effective NS2B-NS3 protease inhibitors with improved potency and bioavailability.
ISSN: 0166-3542
DOI: 10.1016/j.antiviral.2018.10.006
Schools: School of Biological Sciences 
Interdisciplinary Graduate School (IGS) 
Lee Kong Chian School of Medicine (LKCMedicine) 
Organisations: Institute of Structural Biology
Institute of Health Technologies
Rights: © 2018 Elsevier B.V. All rights reserved. This paper was published in Antiviral Research and is made available with permission of Elsevier B.V.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:IGS Journal Articles
LKCMedicine Journal Articles
SBS Journal Articles

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