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

Zheng Zhu,Kin-Hang Kok,Cyril Yip,Shuofeng Yuan,Jie Zhou,Kenn Chik,Hin Chu,Dong-Yan Jin,Terrence Yuen,Lei Wen,Kwok-Yung Yuen,Dong Wang,Feifei Yin,Jasper Chan

doi:10.3390/ijms20020392

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.

Highlights

Zika virus (ZIKV) is a member of the genus Flavivirus in the family Flaviviridae [1]
As the small ubiquitin-like modifier (SUMO) proteins of insects may be different from those of human and mammals, the motifs of these 6 flaviviruses might still be potential SUMO-interacting motif (SIM) for insect SUMO proteins [20]. These genomic data showed that the putative SIM at the N-terminal domain of the non-structural 5 (NS5) protein is highly conserved among flaviviruses
The SUMO Inhibitor 2-D08 Significantly Inhibited the Replication of ZIKV and Other Medically Important Flaviviruses In Vitro. Based on these in silico results, we investigated the biological relevance of SUMO modification of the ZIKV NS5 protein in virus replication by assessing the anti-ZIKV effects of a recently identified SUMO inhibitor (2-D08) in vitro [21]

Summary

Introduction

Zika virus (ZIKV) is a member of the genus Flavivirus in the family Flaviviridae [1]. It is an enveloped virus with a non-segmented, single-stranded, positive-sense RNA genome which measures around 10 kilobases [1]. The ZIKV polyprotein is cleaved into 10 structural and non-structural proteins, with the coding region orders and non-structural protein motifs being arranged in the order of 5’-Capsid-preMembrane-Envelope-NS1-NS2A-NS2B-NS3-NS4A-NS4B-NS5-3’ [1]. More than 80 countries/territories in the Americas, Africa, and Asia have reported evidence of local vector-borne ZIKV transmission [5]

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Results

Conclusion