Structure-function relationship of new peptides activating human Nav1.1

Abstract

Na_v1.1 is an important pharmacological target as this voltage-gated sodium channel is involved in neurological and cardiac syndromes. Channel activators are actively sought to try to compensate for haploinsufficiency in several of these pathologies. Herein we used a natural source of new peptide compounds active on ion channels and screened for drugs capable to inhibit channel inactivation as a way to compensate for decreased channel function. We discovered that JzTx-34 is highly active on Na_v1.1 and subsequently performed a full structure-activity relationship investigation to identify its pharmacophore. These experiments will help interpret the mechanism of action of this and formerly identified peptides as well as the future identification of new peptides. We also reveal structural determinants that make natural ICK peptides active against Na_v1.1 challenging to synthesize. Altogether, the knowledge gained by this study will help facilitate the discovery and development of new compounds active on this critical ion channel target.

Keywords: Automated patch clamp; Biophysics; Cellular assay; Dravet disease; Drug discovery; High-throughput screening; JzTx-34; Lead optimization; Peptide synthesis; Pharmacology; Structural functional relationships; hNa(v)1.1 channel.