The Epithelial Sodium (Na) Channel (ENaC) has a demonstrated role in human taste perception of salt. In order to enable discovery of salt-taste modulating compounds, a screening platform was created by generating cell lines expressing ENaC using Chromocell’s proprietary Chromovert® Technology. In the development of these cell lines, multiple factors were considered including: subunit composition, single nucleotide polymorphisms (SNPs), and post-translational modification by extracellular proteases. As a result, we empirically evaluated 864 different assay conditions, from which 9 distinct targets were selected for the screening platform. Selectivity was confirmed with agents known to inhibit ENaC. High throughput screening and secondary assays identified a number of hit compounds, which included both positive and negative modulators of ENaC activity. We evaluated cell-identified positive modulators using sensory discriminative testing. Although active in cells, dose limits due to off-tastes gave sensory results that were trending but not significant in terms of increase in salt taste perception. However, in combinatorial screening, both in the cellular assay as well as in human sensory testing, we found synergistic effects between cell-identified hit compounds, generating statistically significant results in both cells (cell based activity &gt; 2x either single compound) and in sensory salt taste enhancement (p &lt; 0.05 in 2-alternative forced choice). These results suggest that there may be multiple binding sites for modulation of the constitutively-active ENaC.

Cell based discovery and translation of flavor modulators in salt taste

256th National Meeting (2018)

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