2. Academic Validation
  3. Design, synthesis, and biological evaluation of novel 2'-methyl-2'-fluoro-6-methyl-7-alkynyl-7-deazapurine nucleoside analogs as anti-Zika virus agents

Design, synthesis, and biological evaluation of novel 2'-methyl-2'-fluoro-6-methyl-7-alkynyl-7-deazapurine nucleoside analogs as anti-Zika virus agents

  • Eur J Med Chem. 2022 Apr 15;234:114275. doi: 10.1016/j.ejmech.2022.114275.
Guoqiang Yao 1,  Jianchen Yu 2,  Cai Lin 3,  Yujia Zhu 4,  Anna Duan 3,  Mengfeng Li 5,  Jie Yuan 6,  Jiancun Zhang 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, Guangzhou, 510530, China; University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing, 100049, China.
  • 2 Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China; Guangdong Province Key Laboratory of Functional Molecules in Oceanic Microorganism (Sun Yat-sen University), Bureau of Education, Guangzhou, China; Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • 3 State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, Guangzhou, 510530, China.
  • 4 School of Public Health, Sun Yat-sen University, Guangzhou, China.
  • 5 Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; School of Basic Medical Science, Southern Medical University, Guangzhou, China.
  • 6 Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China; Guangdong Province Key Laboratory of Functional Molecules in Oceanic Microorganism (Sun Yat-sen University), Bureau of Education, Guangzhou, China; Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. Electronic address: [email protected].
  • 7 State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, Guangzhou, 510530, China. Electronic address: [email protected].
PMID: 35306290 DOI: 10.1016/j.ejmech.2022.114275
Abstract

Zika virus (ZIKV) is a mosquito-borne Flavivirus and outbreaks of ZIKV have been reported in Africa, Americas and other parts of the world lately. The ZIKV epidemic has received extensive attention due to its ability to cause serious medical consequences and complications such as microcephaly and Guillain-Barre syndrome in recent years. Up to now, there are no specific treatments or vaccines available for ZIKV Infection, which highlights the urgent need for developing new therapies. In this work, we designed and synthesized a series of novel 6-methyl-7-acetylenenyl-7-deazapurine nucleoside analogs as potential inhibitors of ZIKV replication. The biological activities against ZIKV replication were evaluated and the structure-activity relationship (SAR) was also studied. Among the compounds evaluated, nucleoside analog 38 (EC50 = 2.8 ± 0.8 μM, EC90 = 6.8 ± 2.3 μM) showed the most potent anti-ZIKV activity with low cytotoxicity (CC50 = 54.1 ± 6.9 μM) in an A549 based cellular model. The inhibitory activity of 38 was about 5 times more potent than the positive control NITD008. Notably, 38 showed similar inhibition potency against different ZIKV strains (ZG-01 and MR766) in a variety of host cell types including SNB19, A549, Huh7, Vero. In addition, 38 (Kd = 1.87 μM) has a stronger affinity to ZIKV RNA-dependent RNA polymerase (RdRp) protein than NITD008 (Kd = 3.43 μM) in the non-phosphorylation assay. These results indicated that compound 38 may serve as a promising candidate in future anti-ZIKV drug discovery.

Keywords

7-Deazapurine; Anti-ZIKV; Nucleoside analogs; Zika virus.

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