Rottlerin: Structure Modifications and KCNQ1/KCNE1 Ion Channel Activity
| Autor: | Jasmin Müller, Sivatharushan Sivanathan, Veronika Matschke, Julian A. Schreiber, Janina Schubert, Nathalie Strutz-Seebohm, Marco Lübke, Thang Le Quoc, Guiscard Seebohm, Jürgen Scherkenbeck, Florian Körber |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Pharmacology Xenopus Proteins 01 natural sciences Biochemistry Sudden death Loss of function mutation chemistry.chemical_compound Xenopus laevis mode of action Drug Discovery Repolarization Animals Humans Benzopyrans General Pharmacology Toxicology and Pharmaceutics Mode of action total synthesis Ion channel natural product rottlerin Binding Sites Full Paper 010405 organic chemistry Organic Chemistry Acetophenones Cardiac action potential Full Papers 0104 chemical sciences Molecular Docking Simulation 010404 medicinal & biomolecular chemistry chemistry Ion channel activity Potassium Channels Voltage-Gated KCNQ1 Potassium Channel Oocytes Molecular Medicine Rottlerin potassium channel KCNQ1 activator Protein Binding |
| Zdroj: | Chemmedchem |
| ISSN: | 1860-7187 1860-7179 |
| Popis: | The slow delayed rectifier potassium current (IKs) is formed by the KCNQ1 (Kv7.1) channel, an ion channel of four α‐subunits that modulates KCNE1 β‐subunits. IKs is central to the repolarization of the cardiac action potential. Loss of function mutation reducing ventricular cardiac IKs cause the long‐QT syndrome (LQTS), a disorder that predisposes patients to arrhythmia and sudden death. Current therapy for LQTS is inadequate. Rottlerin, a natural product of the kamala tree, activates IKs and has the potential to provide a new strategy for rational drug therapy. In this study, we show that simple modifications such as penta‐acetylation or penta‐methylation of rottlerin blunts activation activity. Total synthesis was used to prepare side‐chain‐modified derivatives that slowed down KCNQ1/KCNE1 channel deactivation to different degrees. A binding hypothesis of rottlerin is provided that opens the way to improved IKs activators as novel therapeutics for the treatment of LQTS. The polyphenolic natural product rottlerin, isolated from Kamala powder, has been used for centuries in traditional Indian medicine. Among other biological effects, rottlerin has been shown to activate KCNQ1 potassium channels. Rottlerin analogues were synthesized and evaluated electrophysiologically in X. laevis oocytes. A molecular modeling based model was developed to explain the binding‐mode of rottlerin and other KCNQ1 ligands. |
| Databáze: | OpenAIRE |
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