INVESTIGATING THE PRINCIPLES OF CHEMICAL MODULATION ON ION CHANNELS

[摘要] Modulation of ion channels by small molecule drugs or chemicals provides both opportunities and challenges in the drug development process. The molecular interaction between a channel protein and a drug is the basis for both mediating the therapeutic effects on the intended targets; and on the other hand adverse drug reactions due to unintended off-target effects. My thesis research is focused on investigating the basic principles of chemical modulation of ion channels and the physiological consequences of these modulations in native systems such as patient specific derived cardiomyocytes. In my first thesis project, I explored whether small molecule potassium channel activators could play a role in normalizing physiological characteristics of cardiomyocytes from Long QT syndrome (LQTS) patients.LQTS is a genetic disease characterized by a prolonged QT interval in electrocardiogram (ECG) and induced by the reduction of depolarization capacity. I applied quantitative Hodgkin-Huxley modeling analyses to test the effectiveness of different normalization strategies and the modeling predicted results guided our selection process for compound identification. The identified compound was then validated in recombinant systems and eventually evaluated in patient specific induced pluripotent stem cells (iPSCs) based LQTS disease model.My study suggests that gating-specific modulation of hERG (the human Ether-à-go-go-Related Gene) potassium channels couldreverse the disease phenotypes of KCNQ1 mutation induced LQT1 patient derived cardiomyocytes.In my second thesis project, I explored the pharmacological profiles of voltage gated sodium channels (Navs ), which are essential for membrane excitability and are validated therapeutic targets for cardiac arrhythmias, seizure disorders, pain syndromes and neuromuscular diseases.My investigation was specifically focused on molecular mechanism for potential pharmacological promiscuity.In this study, I developed specific mutant channels of Nav1.5 and Nav1.4 to confer persistent calcium permeability, where genetically encoded calcium indicators with different wavelength emission spectra were used for simultaneously reporting of compound activity and site dependence. This study reveals aF1760 residue dependent promiscuity inNav1.5,Nav1.4 and potentially all the eukaryotic Nav channels. This under appreciated promiscuity of blockade ofNavs may deepen our understanding of general molecular mechanisms of drug target promiscuity.

[发布机构] Johns Hopkins University

[效力级别] Chemicals

[关键词] Ion Channels;Chemicals;Biology