Category: Assay Development and Screening
The voltage-gated sodium channel, Nav1.1, highly expressed in fast spiking interneurons (FSIs), initiates the interneuron’s action potentials and promotes γ-oscillations. This process is critical for memory encoding and other cognitive functions. An impaired function of FSIs is associated with disorders like autism, schizophrenia, Alzheimer’s disease and others. Potentiators of Nav1.1 can recover reduced FSI function that might restore γ-oscillations. Therefore, these compounds hold the potential to mitigate cognitive dysfunction in transgenic mice with decreased levels of Nav1.1 expression in parvalbumin-positive neurons.
Nav1.1 gating is complex, and activators of the ion channel can modulate various channel properties. Amongst many different screening techniques available, the patch clamp technique is the only one that reveals mode of action information. Recent advances of patch clamp devices have enabled the technology to be employed in large compound library screens. Qube384 is a second generation automated patch clamp device capable of testing thousands of compounds per day whilst providing true giga-ohm seal quality data. Using the Qube384 in a drug discovery cascade enables acquisition of mode of action data simultaneous with hit detection during the primary screen, minimizing the need for many follow-up validation studies.
In the present work we present an assay for Nav1.1 with constantly high success rates and capable of distinguishing between different modes of action. First we present biophysical characteristics of the assay. Secondly, we pharmacologically validate the assay using the small molecule activator, AA43279. Finally, data of a fully unattended experiment, including 11 consecutively executed 384-well QChips, are presented. Making use of Qube384`s automation capabilities it is possible to screen up to 6400 compounds per day. In summary, this work demonstrates that Qube384 provides a robust method to accelerate the hit-to-lead time for ion channel drug discovery and helps to identify the most relevant compounds faster.
Daniel Sauter– Application Scientist, Sophion Bioscience Inc, Woburn, Massachusetts
Sophion Bioscience Inc
I have worked in the ion channel research field for 8 years. Throughout these years I have been working with many different ion channel targets related to a variety of diseases including cardiology and oncology.