Professor Gao Shuai of Wuhan University cooperated with Professor Yan Ning, and Cell released the latest collaborative research results of drug regulation of calcium ion channels

News Network News (Correspondent Yang Peng) On November 22, Professor Gao Shuai of the School of Pharmacy of Wuhan University and Yan Ning, former Professor of Princeton University, jointly published the latest research results
of drug regulation of calcium ion channels online in Cell (Cell) magazine.

The paper is entitled "Structural basis for the severe adverse interaction of sofosbuvir and amiodarone on L-type Cav channels", through high-resolution cryo-EM, binding cell activity, molecular simulation and other experiments, The molecular mechanism of severe side effects caused by the combination of hepatitis C specific drug sofebuvir and antiarrhythmic drug iodomine was revealed, which laid a structural foundation for the development of safer hepatitis C treatment drugs and brought new enlightenment
to the clinical research of drug side effects.

Gao Shuai and Dr.
Yao Xia, a postdoctoral fellow at Princeton University, are co-first authors, and Gao Shuai and Yan Ning are co-corresponding authors
.

Sofebuvir as a drug targeting hepatitis C virus NS5B polymerase has a cure rate of nearly 100%, and iodomine is an antiarrhythmic drug that mainly works
by inhibiting the ion channels of the heart.
After the combination of sofosbuvir and iodomine, it was found that the patient had severe bradycardia and even a case of death, and after in-depth research, it was found that sofosbuvir or its analogues can enhance the inhibitory effect of iododobuir on L-type calcium ion channels
.

Through the structure of high-resolution cryo-EM, it was found that iodomine was mainly bound to the open window site of the calcium ion channel through hydrophobicity, and its tertiary amine group pointed to the electrostatic interaction between the ion pore and the phosphate group of sofosbuvir, which stabilized sofibbuvir in the ion pore and hindered the passage
of calcium ions.
In addition, we found through cell experiments that sofosbuvir has a synergistic inhibitory effect with iodophenone, no synergistic effect with dihydropyridine hypotensive drugs (nifedipine) inhibition, and a competitive inhibitory effect with the cardiovascular drug verapamil, and we explained the reason
why these two cardiovascular drugs do not produce similar side effects through structural analysis.
More importantly, we found through molecular docking technology that only changing the chirality of sofosbuvir phosphate can break the interaction between molecules and improve the safety of
anti-hepatitis C drugs.

This is another systematic and breakthrough in the field of Gao Shuai since Nature published the mechanism of action of the analgesic drug ziconotide targeting calcium channels in July 2021 and Cell Research in April 2022, showing the positive role of structural biology on drug development and drug evaluation, and laying an important structural foundation
for the research and development of new innovative drugs.

(Editor: Fu Xiaoge)