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

## TL;DR

This study examines how three alkaloids from Fritillaria species affect hERG channels and finds that they can block these channels but also show antagonistic interactions.

## Contribution

The first study to investigate the combination effects of alkaloids from one herb on hERG channels.

## Key findings

- Peiminine and sipeimine block hERG currents with IC50s of 36.8 ± 2.5 μM and 47.6 ± 9.8 μM, similar to peimine.
- Peiminine shows a preference for open or inactivated hERG channel states.
- Antagonistic effects among the three alkaloids may reduce potential cardiotoxicities.

## 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.