F557L – a novel determinant of hERG channel inhibition: allosteric modulation or drug binding?

2013 ◽  
Vol 1 (Suppl. 1) ◽  
pp. A3.12
Author(s):  
Priyanka Saxena
2020 ◽  
Vol 60 (12) ◽  
pp. 6007-6019
Author(s):  
Vishal B. Siramshetty ◽  
Dac-Trung Nguyen ◽  
Natalia J. Martinez ◽  
Noel T. Southall ◽  
Anton Simeonov ◽  
...  

2013 ◽  
Vol 58 (2) ◽  
pp. 820-827 ◽  
Author(s):  
Natalie G. Sanders ◽  
David J. Meyers ◽  
David J. Sullivan

ABSTRACTQuinine and other cinchona-derived alkaloids, although recently supplanted by the artemisinins (ARTs), continue to be important for treatment of severe malaria. Quinine and quinidine have narrow therapeutic indices, and a safer quinine analog is desirable, particularly with the continued threat of antimalarial drug resistance. Hydroxyethylapoquinine (HEAQ), used at 8 g a day for dosing in humans in the 1930s and halving mortality from bacterial pneumonias, was shown to cure bird malaria in the 1940s and was also reported as treatment for human malaria cases. Here we describe synthesis of HEAQ and its novel stereoisomer hydroxyethylapoquinidine (HEAQD) along with two intermediates, hydroxyethylquinine (HEQ) and hydroxyethylquinidine (HEQD), and demonstrate comparable but elevated antimalarial 50% inhibitory concentrations (IC50) of 100 to 200 nM againstPlasmodium falciparumquinine-sensitive strain 3D7 (IC50, 56 nM). Only HEAQD demonstrated activity against quinine-tolerantP. falciparumstrains Dd2 and INDO with IC50s of 300 to 700 nM. HEQD had activity only against Dd2 with an IC50of 313 nM. In the lethal mouse malaria modelPlasmodium bergheiANKA, only HEQD had activity at 20 mg/kg of body weight comparable to that of the parent quinine or quinidine drugs measured by parasite inhibition and 30-day survival. In addition, HEQ, HEQD, and HEAQ (IC50≥ 90 μM) have little to no human ether-à-go-go-related gene (hERG) channel inhibition expressed in CHO cells compared to HEAQD, quinine, and quinidine (hERG IC50s of 27, 42, and 4 μM, respectively). HEQD more closely resembled quininein vitroandin vivoforPlasmodiuminhibition and demonstrated little hERG channel inhibition, suggesting that further optimization and preclinical studies are warranted for this molecule.


2012 ◽  
Vol 66 (2) ◽  
pp. 171
Author(s):  
Giovanni Y. Di Veroli ◽  
Mark Davies ◽  
Chris E. Pollard ◽  
Jean-Pierre Valentin ◽  
Henggui Zhang ◽  
...  

2017 ◽  
Vol 36 (4) ◽  
pp. 314-324 ◽  
Author(s):  
Ling Luo ◽  
Peijing Hu ◽  
Changqing Miao ◽  
Aiqun Ma ◽  
Tingzhong Wang

Clenbuterol, a β2-selective adrenergic receptor agonist, is illicitly used in weight loss and performance enhancement and animal production. Increasing evidence demonstrates that clenbuterol induces various kinds of arrhythmias and QTc interval prolongation. However, little is known about the underlying mechanism. Most drugs are associated with QTc prolongation through interfering with human ether-a-go-go-related gene (hERG) K+ channels. The present study aims to investigate the effects and underlying mechanisms of clenbuterol on the hERG channel. HEK 293 cells were transfected with wild type and Y652A or F656A mutants of the hERG channel and treated with clenbuterol. The hERG current was recorded using whole-cell patch-clamp technique, and protein level was evaluated by Western blot. We found that clenbuterol decreases the mature form of the hERG protein at the cell membrane in a concentration- and time-dependent manner, without affecting the immature form. Correspondingly, clenbuterol chronic treatment reduced hERG current to a greater extent compared to acute treatment. In the presence of Brefeldin A (BFA), which was used to block hERG channel trafficking to cell membrane, clenbuterol reduced hERG on plasma membrane to a greater extent than BFA alone. In addition, the hERG channel’s drug binding sites mutant Y652A and F656A abolished clenbuterol-mediated hERG reduction and current blockade. In conclusion, clenbuterol reduces hERG channel expression and current by promoting the channel degradation. The effect of clenbuterol on the hERG channel is related to the drug-binding sites, Tyr-652 and Phe-656, located on the S6 domain. This biophysical mechanism may underlie clenbuterol-induced QTc prolongation or arrhythmia.


2012 ◽  
Vol 22 (17) ◽  
pp. 5563-5568 ◽  
Author(s):  
Alexander G. Dossetter ◽  
Jonathan Bowyer ◽  
Calum R. Cook ◽  
James J. Crawford ◽  
Jonathan E. Finlayson ◽  
...  

2003 ◽  
Vol 279 (11) ◽  
pp. 10120-10127 ◽  
Author(s):  
David Fernandez ◽  
Azad Ghanta ◽  
Gregory W. Kauffman ◽  
Michael C. Sanguinetti

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