Design, synthesis, and biological evaluation of novel 2'-deoxy-2'-spirooxetane-7-deazapurine nucleoside analogs as anti-SARS-CoV-2 agents

Minli Gao; Zhaoyong Zhang; Guoqiang Yao; Lu Zhang; Anna Duan; Yuanyuan Zhang; Yanqun Wang; Jincun Zhao; Jiancun Zhang

doi:10.1016/j.antiviral.2024.106060

Design, synthesis, and biological evaluation of novel 2'-deoxy-2'-spirooxetane-7-deazapurine nucleoside analogs as anti-SARS-CoV-2 agents

Antiviral Res. 2024 Dec 30:234:106060. doi: 10.1016/j.antiviral.2024.106060. Online ahead of print.

Authors

Minli Gao¹, Zhaoyong Zhang², Guoqiang Yao³, Lu Zhang⁴, Anna Duan³, Yuanyuan Zhang², Yanqun Wang⁵, Jincun Zhao⁶, Jiancun Zhang⁷

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 State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
³ State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, Guangzhou, 510530, China.
⁴ State Key Laboratory of Respiratory Disease, Public Health Safety Center Laboratory of General Administration of Customs, Guangzhou Customs Technology Center, Guangzhou, Guangdong, China.
⁵ State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China. Electronic address: [email protected].
⁶ State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 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; Guangzhou Henovcom Bioscience Inc, 11 Kaiyuan Rd, Guangzhou, Guangdong, China. Electronic address: [email protected].

PMID: 39743047
DOI: 10.1016/j.antiviral.2024.106060

Abstract

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused an unprecedented global public health crisis and continues to pose grave threats to human health. The efficacy of current vaccines and therapeutics is likely limited for future emerging strains due to the highly mutative nature of the virus, underscoring an urgent need for the development of new, potent antiviral agents. In this study, we report the design and synthesis of a series of novel 2'-deoxy-2'-spirooxetane-7-deazapurine nucleoside analogs as potential inhibitors of SARS-CoV-2 replication. Some of these compounds demonstrate potent antiviral activity, offering a potential new weapon for therapeutic intervention against the ever-evolving SARS-CoV-2 virus. Among the tested compounds, nucleoside analog 11q exhibited the most potent antiviral activity against SARS-CoV-2 in Vero E6 cells, with IC₅₀ values of 0.14 μM for the wild-type strain and 0.36 μM for the BA.5 strain. Notably, compound 11q exhibits up to nine times greater inhibitory activity against wild-type SARS-CoV-2 compared to Remdesivir and also possesses a superior selectivity index. These findings suggest that compound 11q is a highly promising lead candidate for future drug development aimed at combating SARS-CoV-2.

Keywords: 2′-deoxy-2′-spirooxetane; 7-Deazapurine; Coronaviruses; Nucleoside analogs; SARS-CoV-2.