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

Qishu Chen; Qifan Zhou; Sidi Yang; Fan Pan; Hongqi Tao; Yuanmei Wen; Yang Chao; Cailing Xie; Weixin Ou; Deyin Guo; Yingjun Li; Xumu Zhang

doi:10.1016/j.bioorg.2024.107894

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

Bioorg Chem. 2024 Dec:153:107894. doi: 10.1016/j.bioorg.2024.107894. Epub 2024 Oct 18.

Authors

Qishu Chen¹, Qifan Zhou², Sidi Yang³, Fan Pan¹, Hongqi Tao¹, Yuanmei Wen¹, Yang Chao¹, Cailing Xie³, Weixin Ou³, Deyin Guo⁴, Yingjun Li⁵, Xumu Zhang⁶

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: [email protected].
³ Guangzhou National Laboratory, Guangzhou, Guangdong Province 510005, China.
⁴ Guangzhou National Laboratory, Guangzhou, Guangdong Province 510005, China. Electronic address: [email protected].
⁵ State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 510180, China. Electronic address: [email protected].
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: [email protected].

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.

MeSH terms

Adenosine* / analogs & derivatives
Adenosine* / chemistry
Adenosine* / pharmacology
Antiviral Agents* / chemical synthesis
Antiviral Agents* / chemistry
Antiviral Agents* / pharmacology
Coronavirus 229E, Human / drug effects
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Exoribonucleases
Humans
Methyltransferases* / antagonists & inhibitors
Methyltransferases* / metabolism
Microbial Sensitivity Tests
Molecular Structure
SARS-CoV-2* / drug effects
Structure-Activity Relationship
Viral Nonstructural Proteins* / antagonists & inhibitors
Viral Nonstructural Proteins* / metabolism

Substances

Adenosine
Antiviral Agents
Methyltransferases
Viral Nonstructural Proteins
NSP14 protein, SARS-CoV-2
Enzyme Inhibitors
Exoribonucleases