2. Academic Validation
  3. hERG Channel Blockade and Antagonistic Interactions of Three Steroidal Alkaloids from Fritillaria Species

hERG Channel Blockade and Antagonistic Interactions of Three Steroidal Alkaloids from Fritillaria Species

  • Molecules. 2025 Sep 25;30(19):3882. doi: 10.3390/molecules30193882.
Hui Lu 1 2 3,  Tingting Hao 1 2 3,  Zixuan Zhang 1 2 3,  Chenxin Jiang 1 2 3,  Jianwei Xu 1 2 3,  Antony Stalin 4,  Wei Zhao 1 2 3
Affiliations

Affiliations

  • 1 National Key Laboratory for Development and Utilization of Forest Food Resources, Zhejiang Agriculture and Forestry University, No. 666, Wusu Street, Hangzhou 311300, China.
  • 2 Zhejiang Provincial Key Laboratory of Resources Protection and Innovation of Traditional Chinese Medicine, Zhejiang Agriculture and Forestry University, No. 666, Wusu Street, Hangzhou 311300, China.
  • 3 School of Food and Health, Zhejiang Agriculture and Forestry University, No. 666, Wusu Street, Hangzhou 311300, China.
  • 4 Institute of Fundamental and Frontier Sciences, University of Electronic Science and Technology of China, No. 4, Section 2, North Jianshe Road, Chengdu 610054, China.
PMID: 41097303 DOI: 10.3390/molecules30193882
Abstract

The bulb of Fritillaria species called "Bei Mu" is a well-known traditional Chinese medicine. We have reported some potential off-target effects of "Bei Mu" due to peimine's blockade of hERG (human Ether-a-go-go-Related Gene) channels. This research investigated the modulatory effects of three major alkaloid analogs of "Bei Mu" and their cooperative effects on hERG channels using manual whole-cell patch-clamp techniques. Results showed that peiminine and sipeimine blocked hERG currents with IC50s of 36.8 ± 2.5 μM and 47.6 ± 9.8 μM, which were close to that of peimine (26.1 ± 3.5 μM). Peiminine-induced blockade increased with increasing depolarizing strengths, durations, and frequencies, which suggested a preferential binding to open or inactivated states. The reduced blockade by the less inactivating S631A mutation supported peiminine's inactivation preference. Molecular docking and dynamics simulations confirmed the hERG-blocking activities of the three Alkaloids and provided further insight into potential mechanisms. We also discovered antagonistic effects of the three Alkaloids at nearly all concentrations tested, which might help reduce potential cardiotoxicities. To our knowledge, this is the first study to investigate combination effects of chemicals from one herb on hERG channels. In conclusion, peiminine and sipeimine can block hERG channels in a way similar to peimine, but antagonistic effects exist among them.

Keywords

Bei Mu; Fritillaria; MD simulation; alkaloids; hERG; hERG-blockade.

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