Novel Nucleoside Analogs Developed as Anti-Zika Virus Agents

Zika virus (ZIKV) is a mosquito-borne RNA virus belonging to the Flaviviridae family. In recent years, Zika outbreaks have been reported in Africa, America, and many other parts of the world. Such pandemic is threatening many people’s life and health by causing serious complications such as abnormal smallness of the head and Guillain-Barré syndrome. That there are no specific treatments or vaccines available for ZIKV infection yet underlines the urgency of developing new therapies.  

A research group, led by ZHANG Jiancun, principle investigator from Guangzhou Institutes of Biomedicine and Health (GIBH) of Chinese Academy of Sciences and Professor YUAN Jie from Sun Yat-Sen University, has developed a series of novel nucleoside anologs for the potential treatment for ZIKV infection and found that some of them were promising leads for the development of anti-ZIKV therapeutics. 

This work was published in Eur. J. Med. Chem. on March 17, 2022. 

The group designed and synthesized new 6-methyl-7-acetylenenyl-7-deazapurine nucleoside analogs as potential inhibitors of ZIKV replication. Taking the 6-methyl-7-phenylethynyl-7-deazapurine analog as the lead compound, which was obtained in the previous research, they modified the ethynyl group (linker) and the phenyl group (R) at 7-position of deazapurine to improve the anti-ZIKV activities. 

Afterwards, they evaluated different compounds’ biological activities against ZIKV replication, and studied their structure-activity relationship (SAR) via a titer assay. The inhibitory activity of newly prepared compounds was assessed against ZIKV with NITD008, a 7-deazaadenosine analog, as the positive control. 

The results revealed that among all the compounds, the nucleoside analog 3b13 showed the most potent anti-ZIKV activity with low cytotoxicity in an A549 based cellular model. 

In comparison with the positive control NITD008, 3b13 had the inhibitory activity about five times more potent, and demonstrated a stronger binding affinity to ZIKV RNA-dependent RNA polymerase, which was an important therapeutic target in RNA virus-caused diseases. 

Furthermore, the compound exhibited the similar inhibition potency against different ZIKV strains (ZG-01 and MR766) in a variety of host cell types including SNB19, A549, Huh7, and Vero. 

Those findings indicated that Compound 3b13 may help the advancement of future anti-ZIKV drug. 

The research was funded by China Evergrande Group (2020GIRHHMS08) and the State Key Laboratory of Anti-Infective Drug Development (Grant SKLAID201805). 

Novel Nucleoside Analogs Developed as Anti-Zika Virus Agents （By GIBH）

Contact: 

ZHANG Jiancun 

Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences   

E-mail: zhang_jiancun@gibh.ac.cn