2. Academic Validation
  3. Synthesis and evolution of 16-membered macrolide carrimycin derivatives as a novel class of anti-HCoV-OC43 agents targeting viral FSE RNA

Synthesis and evolution of 16-membered macrolide carrimycin derivatives as a novel class of anti-HCoV-OC43 agents targeting viral FSE RNA

  • Eur J Med Chem. 2025 Apr 5:287:117373. doi: 10.1016/j.ejmech.2025.117373.
Xiuli Zhong 1,  Zhihui Yu 1,  Runze Meng 1,  Yue Gong 1,  Jianrui Li 1,  Weiqing He 1,  Hongying Li 1,  Jiayu Li 1,  Zhiyun Wu 1,  Qionglu Duan 1,  Yinghong Li 1,  Yonghua Liu 2,  Zonggen Peng 3,  Danqing Song 4
Affiliations

Affiliations

  • 1 Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100050, China.
  • 2 Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100050, China. Electronic address: liuyonghua@imb.pumc.edu.cn.
  • 3 Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100050, China. Electronic address: pengzonggen@imb.pumc.edu.cn.
  • 4 Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100050, China. Electronic address: songdanqing@imb.pumc.edu.cn.
PMID: 39952097 DOI: 10.1016/j.ejmech.2025.117373
Abstract

We first demonstrate that carrimycin, as an Antibiotic, shows broad-spectrum anti-coronavirus activity by targeting frameshifting element (FSE) RNA. Herein, taking carrimycin as the lead, 26 new 16-membered macrolides were synthesized and evaluated for Antiviral activity against coronavirus strains. Compound 2d exhibited the elevated Antiviral efficacy against HCoV-OC43 and HCoV-229E with EC50 values of 0.85 μM and 1.45 μM by directly targeting coronaviral FSE RNA pseudoknot. Molecular simulations revealed that the introduction of a 4″-substituent transforms the macrocyclic core into U-shaped conformation, enabling the higher binding with FSE. Meanwhile, using thermal proteome profiling (TPP) technology, we identified DIS3L2 as a potential host target, which probably assisted 2d to exert the Antiviral effect. Therefore, the 16-membered macrolides constituted a new class of RNA inhibitors against coronaviruses, and 2d owns a dual-target mechanism that acts on both viral FSE RNA and host DIS3L2.

Keywords

Anti-coronavirus; Carrimycin derivatives; DIS3L2; FSE RNA; Synthesis.

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