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Identification of RdRp-NiRAN/JAK1 Dual-Target Drugs for COVID-19 Treatment
Huixuan Zhao1, Xiaoyu Chang2, Lei Sun3
1Institute of Frontier Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Qingdao 266237, China.
The Journal of Physical Chemistry. B
|December 3, 2024
Summary
Azvudine and Citicoline show potential as dual-target COVID-19 drugs. Azvudine inhibits both RNA-dependent RNA polymerase (RdRp) and Janus kinase 1 (JAK1), offering a new treatment mechanism.
Area of Science:
- Virology
- Immunology
- Drug Discovery
Background:
- Severe COVID-19 requires inhibiting virus replication and inflammation.
- RNA-dependent RNA polymerase (RdRp) is crucial for SARS-CoV-2 replication.
- Janus kinase 1 (JAK1) inhibitors have immunosuppressive effects.
Purpose of the Study:
- To evaluate 31 nucleoside drugs for dual inhibition of the RdRp NiRAN domain and JAK1.
- To identify novel RdRp/JAK1 dual-target drugs for COVID-19 treatment.
Main Methods:
- Molecular docking with conformer-dependent charges (MDCC) was applied to 31 nucleoside drugs.
- Molecular dynamics simulations and experimental assays (thermal shift, HTRF) were used for verification.
Main Results:
- Azvudine and Citicoline exhibited strong predicted binding affinities to both NiRAN and JAK1.
- Experimental validation confirmed Azvudine as an RdRp-NiRAN/JAK1 dual-target drug.
Conclusions:
- Azvudine presents a novel mechanism for COVID-19 treatment by targeting both RdRp-NiRAN and JAK1.
- This study proposes a design strategy for developing new RdRp-NiRAN/JAK1 dual-target nucleoside therapeutics.
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