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Targeting SUMO Modification of the Non-Structural Protein 5 of Zika Virus as a Host-Targeting Antiviral Strategy

1
State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China
2
Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China
3
Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Hainan Medical University, Haikou, Hainan, and The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China
4
Department of Pathogen Biology, Hainan Medical University, Haikou, Hainan 571101, China
5
Key Laboratory of Translational Tropical Medicine, Hainan Medical University, Haikou, Hainan 571101, China
6
School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China
7
Carol Yu Centre for Infection, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China
8
The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work as co-first authors.
Int. J. Mol. Sci. 2019, 20(2), 392; https://doi.org/10.3390/ijms20020392
Received: 7 December 2018 / Revised: 14 January 2019 / Accepted: 15 January 2019 / Published: 17 January 2019
(This article belongs to the Special Issue Molecular Research in Emerging Viruses 2019)
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Abstract

Post-translational modifications of host or viral proteins are key strategies exploited by viruses to support virus replication and counteract host immune response. SUMOylation is a post-translational modification process mediated by a family of ubiquitin-like proteins called small ubiquitin-like modifier (SUMO) proteins. Multiple sequence alignment of 78 representative flaviviruses showed that most (72/78, 92.3%) have a putative SUMO-interacting motif (SIM) at their non-structural 5 (NS5) protein’s N-terminal domain. The putative SIM was highly conserved among 414 pre-epidemic and epidemic Zika virus (ZIKV) strains, with all of them having a putative SIM core amino acid sequence of VIDL (327/414, 79.0%) or VVDL (87/414, 21.0%). Molecular docking predicted that the hydrophobic SIM core residues bind to the β2 strand of the SUMO-1 protein, and the acidic residues flanking the core strengthen the binding through interactions with the basic surface of the SUMO protein. The SUMO inhibitor 2-D08 significantly reduced replication of flaviviruses and protected cells against ZIKV-induced cytopathic effects in vitro. A SIM-mutated ZIKV NS5 failed to efficiently suppress type I interferon signaling. Overall, these findings may suggest SUMO modification of the viral NS5 protein to be an evolutionarily conserved post-translational modification process among flaviviruses to enhance virus replication and suppress host antiviral response. View Full-Text
Keywords: antiviral; flavivirus; inhibitor; interferon; NS5; post-translational modification; SUMO; Zika antiviral; flavivirus; inhibitor; interferon; NS5; post-translational modification; SUMO; Zika
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Zhu, Z.; Chu, H.; Wen, L.; Yuan, S.; Chik, K. .-H.; Yuen, T. .-T.; Yip, C. .-Y.; Wang, D.; Zhou, J.; Yin, F.; Jin, D.-Y.; Kok, K.-H.; Yuen, K.-Y.; Chan, J. .-W. Targeting SUMO Modification of the Non-Structural Protein 5 of Zika Virus as a Host-Targeting Antiviral Strategy. Int. J. Mol. Sci. 2019, 20, 392.

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