[R01] Therapeutic small molecule modulation of Kv channels
Ente: National Institute of Neurological Disorders and Stroke
Scadenza: 2030-07-31
Importo max: 494.045 EUR
Paese: US
Descrizione
Project Summary
Neuronal Kv7 (KCNQ) and Kv1 (KCNA1) subfamily voltage-gated potassium (Kv) channel loss-of-function
causes developmental epileptic encephalopathy, ataxia, hereditary spastic paraplegia (HSP) and addiction. In
this project we focus on the mechanistic basis and potential therapeutic utility of plant-derived diterpenes and
hydroxybenzoic acids that are extremely well tolerated in rodent and human safety studies, cross the blood-
brain-barrier, and which we recently discovered to be potent, efficacious openers of neuronal Kv7 and Kv1
channels. Addiction and epilepsy represent major health burdens in the US and globally, and new approaches
to their treatment are desperately warranted. Episodic ataxia and HSP are relatively rare and therefore can
especially benefit from therapeutic development in academia; in turn, treatments developed for episodic ataxia
can inform development of therapies for epilepsy and potentially other forms of ataxia. In this project we take a
multidisciplinary approach incorporating molecular dynamics (MD) simulations, site-directed mutagenesis,
electrophysiology, and in vivo testing in existing and novel mouse models. In Aim 1, we will pursue the molecular
basis of action and isoform selectivity of the diterpene carnosic acid (CA), which we recently discovered to be a
highly efficacious and isoform-selective Kv7.3/5 channel opener, and to Kv7.3/5-dependently inhibit cocaine-
seeking behavior in mice. We now intend to delineate how CA opens Kv7.3 but not Kv7.2 using all-atom MD
simulations, mutagenesis and electrophysiology. We propose similar studies for gentisic acid (GTA), a
hydroxybenzoic acid we recently found to be the most potent known opener of Kv7.3 and Kv7.2/3. The studies
are translationally highly significant because of the potential for CA to treat psychotropic drug addiction, and for
GTA as a lead anticonvulsant compound. In Aim 2, we will determine the molecular basis of action of pisiferic
acid (PA) and gallic acid (GA), another diterpene and hydroxybenzoic acid, respectively, that we found to be
novel Kv1.1/Kv1.2 channel openers that can reverse the effects of Kv1.1 and Kv1.2 mutations that cause ataxia,
epilepsy and HSP. We will use experimentally validated MD simulations of entire Kv1.1 and Kv1.2 channels in
model neuronal lipid membranes, to determine how PA and GA achieve efficacy, potency and selectivity.
Extensive preliminary data support an exciting paradigm in which PA co-opts the Kv1.1 voltage sensor to act as
a ligand-binding/gating domain. We will also test the ability of PA and GA to rescue in vitro a broader panel of
ataxia, epilepsy, and HSP-linked Kv1.1 and/or Kv1.2 mutants. We have already discovered that PA reverses
EA1 in vivo in our new mouse model of Kv1.1-linked Episodic Ataxia Type 1 (EA1). In Aim 3, we will conduct in
vivo testing of the therapeutic efficacy of PA and GA in mouse models of EA1 and Kv1.2-linked
ataxia/epilepsy/HSP, and PK studies. The project will uncover t
Istituzione: UNIVERSITY OF CALIFORNIA-IRVINE
PI: Geoffrey W Abbott
Progetto: 5R01NS107671-07
Settori: National Institute of Neurological Disorders and Stroke
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