• SyncroPatch 384/768PE

    APC with highest throughput on the market
  • SyncroPatch 384/768PE

    384 cells in parallel => upgradable to 768
  • SyncroPatch 384/768PE

    True HTS AND Gigaohm seals
  • SyncroPatch 384/768PE

    True internal perfusion with continuous data acquisition
  • SyncroPatch 384/768PE

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2018 - Mechanism-specific assay design facilitates the discovery of Nav1.7-selective inhibitors

icon sp96  SyncroPatch 768PE publication in PNAS

Authors: 
Chernov-Rogan T., Li T., Lu G., Verschoof H., Khakh K., Jones S.W., Beresini M.H., Liu C., Ortwine D.F., McKerrall S.J., Hackos D.H., Sutherlin D., Cohen C.J., and Chen J.

Journal: 
PNAS (2018) Early Edition doi: 10.1073/pnas.1713701115


Abstract: 

Many ion channels, including Nav1.7, Cav1.3, and Kv1.3, are linked to human pathologies and are important therapeutic targets. To develop efficacious and safe drugs, subtype-selective modulation is essential, but has been extremely difficult to achieve. We postulate that this challenge is caused by the poor assay design, and investigate the Nav1.7 membrane potential assay, one of the most extensively employed screening assays in modern drug discovery. The assay uses veratridine to activate channels, and compounds are identified based on the inhibition of veratridine-evoked activities. We show that this assay is biased toward nonselective pore blockers and fails to detect the most potent, selective voltage-sensing domain 4 (VSD4) blockers, including PF-05089771 (PF-771) and GX-936. By eliminating a key binding site for pore blockers and replacing veratridine with a VSD-4 binding activator, we directed the assay toward non–pore-blocking mechanisms and discovered Nav1.7-selective chemical scaffolds. Hence, we address a major hurdle in Nav1.7 drug discovery, and this mechanistic approach to assay design is applicable to Cav3.1, Kv1.3, and many other ion channels to facilitate drug discovery.


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