期刊
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
卷 190, 期 -, 页码 178-188出版社
ELSEVIER
DOI: 10.1016/j.ijbiomac.2021.08.121
关键词
Zika virus; G-quadruplex binder; G-quadruplex binding affinity and stability; Antiviral activity; Mechanism
The study indicates that the G-quadruplex binder PDS can serve as a multi-target ZIKV inhibitor with high antiviral activity, effectively suppressing ZIKV replication and protein expression, and reducing ZIKV catalytic activity.
At present, there are still no anti-Zika virus (ZIKV) drugs or vaccines approved by FDA with accurate targets and antiviral mechanisms. Considering the RNA G-quadruplex sequences in ZIKV genome, it is very meaningful to develop G-quadruplex binders as potential anti-ZIKV drugs with novel and accurate targets. In this paper, five classical G-quadruplex binders including Ber, Braco 19, NiL, 360A and PDS have been chosen to discuss their interaction with ZIKV RNA G-quadruplexes. PDS shows higher binding affinity and thermal stability than the other G-quadruplex binders. This property is further evidenced in cells by immunofluorescence microscopy. And PDS shows higher anti-ZIKV activity (EC50 = 4.2 +/- 0.4 mu M) than the other G-quadruplex binders as well as the positive control ribavirin, with a low cytotoxicity. By time-of-addition assay, PDS exerts antiviral activity at the post-entry process of ZIKV replication cycle, thus inhibiting ZIKV mRNA replication and protein expression. Furthermore, PDS combines with ZIKV NS2B-NS3 protease and reduces its catalytic activity. This study suggests that G-quadruplex binder PDS is an effective multi-target ZIKV inhibitor, which provides more guidance to design some novel anti-ZIKV drugs targeting ZIKV RNA G-quadruplexes.
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