2. Academic Validation
  3. Identification of adenosine analogues as nsp14 N7‑methyltransferase inhibitors for treating coronaviruses infection

Identification of adenosine analogues as nsp14 N7‑methyltransferase inhibitors for treating coronaviruses infection

  • Bioorg Chem. 2024 Oct 18:153:107894. doi: 10.1016/j.bioorg.2024.107894.
Qishu Chen 1,  Qifan Zhou 2,  Sidi Yang 3,  Fan Pan 1,  Hongqi Tao 1,  Yuanmei Wen 1,  Yang Chao 1,  Cailing Xie 3,  Weixin Ou 3,  Deyin Guo 4,  Yingjun Li 5,  Xumu Zhang 6
Affiliations

Affiliations

  • 1 Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, College of Science, Academy for Advanced Interdisciplinary Studies and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen, Guangdong 518000, China.
  • 2 Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, College of Science, Academy for Advanced Interdisciplinary Studies and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen, Guangdong 518000, China. Electronic address: zhouqf@sustech.edu.cn.
  • 3 Guangzhou National Laboratory, Guangzhou, Guangdong Province 510005, China.
  • 4 Guangzhou National Laboratory, Guangzhou, Guangdong Province 510005, China. Electronic address: guo_deyin@gzlab.ac.cn.
  • 5 State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 510180, China. Electronic address: liyjun@gzhmu.edu.cn.
  • 6 Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, College of Science, Academy for Advanced Interdisciplinary Studies and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen, Guangdong 518000, China. Electronic address: zhangxm@sustech.edu.cn.
PMID: 39490138 DOI: 10.1016/j.bioorg.2024.107894
Abstract

Coronaviruses are RNA viruses that have coevolved with humans and Animals over time, exhibiting high mutation rates and mortality rates upon epidemic outbreaks. The nonstructural protein (nsp14) is crucial for various coronaviruses processes, including genome replication, protein translation, virus particle assembly, and evasion of host immunity via RNA methylation modification. In this study, a series of adenosine analogs were designed, synthesized, and evaluated for their inhibitory activities. Among them, MTI013 exhibited the strongest nsp14 MTase inhibition and Antiviral activity, with an IC50 of 10.33 μM in HCoV-229E-infected Huh7 cells, along with low cytotoxicity. When combined with the RdRp inhibitor ATV014, MTI013 showed a synergistic Antiviral effect, indicating its potential both as a standalone therapy and in combination treatments. Furthermore, MTI013 displayed high selectivity against the SARS-CoV-2 nsp10-nsp16 complex and five human methyltransferases. These results offer valuable structural insights for future exploration of nsp14 as a drug target for SARS-CoV-2 and Other coronaviruses.

Keywords

Anti-coronavirus; Combination therapy; Coronavirus; Immune escape; nsp14 MTase inhibitor.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-159890
    SARS-CoV-2 nsp14 Mtase Inhibitor