Int J Mol Sci. 2019 Jan 17;20(2). pii: E392. doi: 10.3390/ijms20020392.
Targeting SUMO Modification of the Non-Structural Protein 5 of Zika Virus as a Host-Targeting Antiviral Strategy.
Zhu Z1,2, Chu H3,4, Wen L5, Yuan S6,7, Chik KK8, Yuen TT9, Yip CC10, Wang D11, Zhou J12,13, Yin F14,15,16, Jin DY17, Kok KH18,19, Yuen KY20,21,22,23,24, Chan JF25,26,27,28.
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.
KEYWORDS:
NS5; SUMO; Zika; antiviral; flavivirus; inhibitor; interferon; post-translational modification- PMID:
- 30658479
- PMCID:
- PMC6359730
- DOI:
- 10.3390/ijms20020392
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