Venom Peptides with Dual Modulatory Activity on the Voltage-Gated Sodium Channel NaV1.1 Provide Novel Leads for Development of Antiepileptic Drugs

Voltage-gated sodium (Na_V) channels play a fundamental role in normal neurological function, especially via the initiation and propagation of action potentials. The Na_V1.1 subtype is found in inhibitory interneurons of the brain and it is essential for maintaining a balance between excitation and inhibition in neuronal networks. Heterozygous loss-of-function mutations of SCN1A, the gene encoding Na_V1.1, underlie Dravet syndrome (DS), a severe pediatric epilepsy. We recently demonstrated that selective inhibition of Na_V1.1 inactivation prevents seizures and premature death in a mouse model of DS. Thus, selective modulators of Na_V1.1 might be useful therapeutics for treatment of DS as they target the underlying molecular deficit. Numerous scorpion-venom Peptides have been shown to modulate the activity of Na_V channels, but little is known about their activity at Na_V1.1. Here we report the isolation, sequence, three-dimensional structure, recombinant production, and functional characterization of two peptidic modulators of Na_V1.1 from venom of the buthid scorpion Hottentotta jayakari. These Peptides, Hj1a and Hj2a, are potent agonists of Na_V1.1 (EC₅₀ of 17 and 32 nM, respectively), and they present dual α/β activity by modifying both the activation and inactivation properties of the channel. NMR studies of rHj1a indicate that it adopts a cystine-stabilized αβ fold similar to known scorpion toxins. Although Hj1a and Hj2a have only limited selectivity for Na_V1.1, their unusual dual mode of action provides an alternative approach to the development of selective Na_V1.1 modulators for the treatment of DS.