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
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
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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