2. Academic Validation
  3. Discovery and development of novel 10,12-disubstituted aloperine derivatives against HCoV-OC43 by targeting allosteric site of host TMPRSS2

Discovery and development of novel 10,12-disubstituted aloperine derivatives against HCoV-OC43 by targeting allosteric site of host TMPRSS2

  • Bioorg Chem. 2024 Jun:147:107317. doi: 10.1016/j.bioorg.2024.107317.
Runze Meng 1,  Xiuli Zhong 1,  Yue Gong 1,  Yulong Shi 1,  Jiayu Li 1,  Zhiyun Wu 1,  Qionglu Duan 1,  Xintong Zhang 1,  Yuheng Mei 1,  Jingyang Zhu 1,  Zonggen Peng 1,  Yinghong Li 2,  Danqing Song 3
Affiliations

Affiliations

  • 1 Beijing Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China.
  • 2 Beijing Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China. Electronic address: liyinghong@imb.pumc.edu.cn.
  • 3 Beijing Key Laboratory of Bioactive Substances and Functions of Natural Medicines, 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: 38583252 DOI: 10.1016/j.bioorg.2024.107317
Abstract

By inducing steric activation of the 10CH bond with a 12-acyl group to form a key imine oxime intermediate, 20 novel (10S)-10,12-disubstituted aloperine derivatives were successfully synthesized and assessed for their Antiviral efficacy against HCoV-OC43. Of them, compound 3i exhibited the moderate activities against HCoV-OC43, as well as against the SARS-CoV-2 variant EG.5.1 with the comparable EC50 values of 4.7 and 4.1 μM. A mechanism study revealed that it inhibited the Protease activity of host TMPRSS2 by binding to an allosteric site, rather than the known catalytic center, different from that of camostat. Also, the combination of compound 3i and molnupiravir, as an RdRp inhibitor, showed an additive Antiviral effect against HCoV-OC43. The results provide a new binding mode and lead compound for targeting TMPRSS2, with an advantage in combating broad-spectrum coronavirus.

Keywords

12N-Acyl disubstituted aloperines; Allosteric site; HCoV-OC43; Synthesis; TMPRSS2.

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