Cepharanthine analogs mining and genomes of Stephania accelerate anti-coronavirus drug discovery

Liang Leng, Zhichao Xu, Bixia Hong, Binbin Zhao, Ya Tian, Can Wang, Lulu Yang, Zhongmei Zou, Lingyu Li, Ke Liu, Wanjun Peng, Jiangning Liu, Zhoujie An, Yalin Wang, Baozhong Duan, Zhigang Hu, Chuan Zheng, Sanyin Zhang, Xiaodong Li, Maochen Li, Zhaoyu Liu, Zenghao Bi, Tianxing He, Baimei Liu, Huahao Fan (), Chi Song (), Yigang Tong () and Shilin Chen ()
Additional contact information
Liang Leng: Chengdu University of Traditional Chinese Medicine
Zhichao Xu: Northeast Forestry University
Bixia Hong: Beijing University of Chemical Technology
Binbin Zhao: NHC Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College
Ya Tian: Northeast Forestry University
Can Wang: Chengdu University of Traditional Chinese Medicine
Lulu Yang: Chengdu University of Traditional Chinese Medicine
Zhongmei Zou: Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College
Lingyu Li: Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College
Ke Liu: Beijing University of Chemical Technology
Wanjun Peng: NHC Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College
Jiangning Liu: NHC Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College
Zhoujie An: Northeast Forestry University
Yalin Wang: Northeast Forestry University
Baozhong Duan: Dali University
Zhigang Hu: Hubei University of Chinese Medicine
Chuan Zheng: Hospital of Chengdu University of Traditional Chinese Medicine
Sanyin Zhang: Chengdu University of Traditional Chinese Medicine
Xiaodong Li: Wuhan Botanical Garden, Chinese Academy of Sciences
Maochen Li: Beijing University of Chemical Technology
Zhaoyu Liu: Chengdu University of Traditional Chinese Medicine
Zenghao Bi: Chengdu University of Traditional Chinese Medicine
Tianxing He: Chengdu University of Traditional Chinese Medicine
Baimei Liu: Chengdu University of Traditional Chinese Medicine
Huahao Fan: Beijing University of Chemical Technology
Chi Song: Chengdu University of Traditional Chinese Medicine
Yigang Tong: Beijing University of Chemical Technology
Shilin Chen: Chengdu University of Traditional Chinese Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Cepharanthine is a secondary metabolite isolated from Stephania. It has been reported that it has anti-conronaviruses activities including severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Here, we assemble three Stephania genomes (S. japonica, S. yunnanensis, and S. cepharantha), propose the cepharanthine biosynthetic pathway, and assess the antiviral potential of compounds involved in the pathway. Among the three genomes, S. japonica has a near telomere-to-telomere assembly with one remaining gap, and S. cepharantha and S. yunnanensis have chromosome-level assemblies. Following by biosynthetic gene mining and metabolomics analysis, we identify seven cepharanthine analogs that have broad-spectrum anti-coronavirus activities, including SARS-CoV-2, Guangxi pangolin-CoV (GX_P2V), swine acute diarrhoea syndrome coronavirus (SADS-CoV), and porcine epidemic diarrhea virus (PEDV). We also show that two other genera, Nelumbo and Thalictrum, can produce cepharanthine analogs, and thus have the potential for antiviral compound discovery. Results generated from this study could accelerate broad-spectrum anti-coronavirus drug discovery.

Date: 2024
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DOI: 10.1038/s41467-024-45690-5

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