Development of a selective inhibitor for Kv1.1 channels prevalent in demyelinated nerves

Al-Sabi, Ahmed; Daly, Declan; Rooney, Myles; Hughes, Cian; Kinsella, Gemma K.; Kaza, Seshu Kumar; Nolan, Kieran; Dolly, J. Oliver

doi:10.1016/j.bioorg.2020.103918

Cited by 3 publications

(4 citation statements)

References 29 publications

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“…Kv1.1 α subunits form heteromeric tetramers with other Kv1 subfamily α subunits, including Kv1.2, in the extraparanodal region of axons and some terminals, in the hippocampus (perforant input from entorhinal cortex, mossy fiber projections from granule cells to CA3, and CA3 axon collaterals) 7 – 11 . We therefore tested effects of gallic acid on Kv1.1/Kv1.2 heteromers generated in oocytes by co-injection of 1:1:2 parts Kv1.1:Kv1.1-E283K:Kv1.2 or Kv1.1:Kv1.1-L155P:Kv1.2 cRNA to approximate the Kv1.1/Kv1.2 heteromeric channel composition in EA1 patients heterozygous for either mutant KCNA1 allele.…”

Section: Resultsmentioning

confidence: 99%

“…Kv channels form as tetramers of pore-forming α subunits, with heteromeric formation often occurring, typically with isoforms of the same subfamily. Kv1.1 can form homomeric channels in vitro, but is thought to almost exclusively form heteromeric channels in neurons in vivo, e.g., with Kv1.2; one exception is that homomeric Kv1.1 occurs in demyelinated neurons, such as in multiple sclerosis 7 – 11 . The normal function of Kv1.1/Kv1.2 channels at juxtaparanodal regions and branch points of myelinated axons helps maintain normal neuromuscular transmission and limit abnormal axonal firing 12 – 14 , with these controls being compromised by pharmacological inhibition or by loss-of-function mutations 10 .…”

Section: Introductionmentioning

confidence: 99%

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Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain

et al. 2023

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There are currently no drugs known to rescue the function of Kv1.1 voltage-gated potassium channels carrying loss-of-function sequence variants underlying the inherited movement disorder, Episodic Ataxia 1 (EA1). The Kwakwaka’wakw First Nations of the Pacific Northwest Coast used Fucus gardneri (bladderwrack kelp), Physocarpus capitatus (Pacific ninebark) and Urtica dioica (common nettle) to treat locomotor ataxia. Here, we show that extracts of these plants enhance wild-type Kv1.1 current, especially at subthreshold potentials. Screening of their constituents revealed that gallic acid and tannic acid similarly augment wild-type Kv1.1 current, with submicromolar potency. Crucially, the extracts and their constituents also enhance activity of Kv1.1 channels containing EA1-linked sequence variants. Molecular dynamics simulations reveal that gallic acid augments Kv1.1 activity via a small-molecule binding site in the extracellular S1-S2 linker. Thus, traditional Native American ataxia treatments utilize a molecular mechanistic foundation that can inform small-molecule approaches to therapeutically correcting EA1 and potentially other Kv1.1-linked channelopathies.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain

et al. 2023

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“…It is possible that the anti-obesity effects observed in Upadhyay et al’s work are due in part to Kv1.1 block. This would need to be tested with a selective Kv1.1 blocker [ 71 ]. A third possibility is that ShK-186, but not ShK-235 or Vm24, can access the olfactory bulb, as resistance to diet-induced obesity is olfactory bulb-dependent [ 72 , 73 ].…”

Section: Discussionmentioning

confidence: 99%

“…Second, Upadhyay et al used ShK-186 rather than ShK-235, a different analog of the ShK toxin. Its single metabolite, the dephosphorylated form of ShK-186, called ShK-198 [30], is not selective for Kv1.3 over Kv1.1 compared with ShK-235 and Vm24 [17,70] This would need to be tested with a selective Kv1.1 blocker [71]. A third possibility is that ShK-186, but not ShK-235 or Vm24, can access the olfactory bulb, as resistance to diet-induced obesity is olfactory bulb-dependent [72,73].…”

Section: Discussionmentioning

confidence: 99%

Adeno-Associated virus 8 delivers an immunomodulatory peptide to mouse liver more efficiently than to rat liver

et al. 2023

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Targeting the Kv1.3 potassium channel has proven effective in reducing obesity and the severity of animal models of autoimmune disease. Stichodactyla toxin (ShK), isolated from the sea anemone Stichodactyla helianthus, is a potent blocker of Kv1.3. Several of its analogs are some of the most potent and selective blockers of this channel. However, like most biologics, ShK and its analogs require injections for their delivery, and repeated injections reduce patient compliance during the treatment of chronic diseases. We hypothesized that inducing the expression of an ShK analog by hepatocytes would remove the requirement for frequent injections and lead to a sustained level of Kv1.3 blocker in the circulation. To this goal, we tested the ability of Adeno-Associated Virus (AAV)8 vectors to target hepatocytes for expressing the ShK analog, ShK-235 (AAV-ShK-235) in rodents. We designed AAV8 vectors expressing the target transgene, ShK-235, or Enhanced Green fluorescent protein (EGFP). Transduction of mouse livers led to the production of sufficient levels of functional ShK-235 in the serum from AAV-ShK-235 single-injected mice to block Kv1.3 channels. However, AAV-ShK-235 therapy was not effective in reducing high-fat diet-induced obesity in mice. In addition, injection of even high doses of AAV8-ShK-235 to rats resulted in a very low liver transduction efficiency and failed to reduce inflammation in a well-established rat model of delayed-type hypersensitivity. In conclusion, the AAV8-based delivery of ShK-235 was highly effective in inducing the secretion of functional Kv1.3-blocking peptide in mouse, but not rat, hepatocytes yet did not reduce obesity in mice fed a high-fat diet.

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An Approach to Pharmacological Targets of Pyrrole Family From Medicinal Chemistry Viewpoint

Moghadam

Mireskandari

Abdel‐Jalil

et al. 2022

MRMC

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Pyrrole is one of the most widely used heterocycles in the pharmaceutical industry. Due to the importance of pyrrole structure in drug design and development, herein, we tried to conduct an extensive review of the bioactive pyrrole based compounds reported recently. The bioactivity of pyrrole derivatives varies, so in the review, we categorized them based on their direct pharmacologic targets. Therefore, readers are able to find the variety of biologic targets for pyrrole containing compounds easily. This review explains around seventy different biologic targets for pyrrole based derivatives, so, it is helpful for medicinal chemists in design and development novel bioactive compounds for different diseases. This review presents an extensive meaningful structure activity relationship for each reported structure as much as possible. The review focuses on papers published between 2018 and 2020.

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Development of a selective inhibitor for Kv1.1 channels prevalent in demyelinated nerves

Cited by 3 publications

References 29 publications

Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain

Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain

Adeno-Associated virus 8 delivers an immunomodulatory peptide to mouse liver more efficiently than to rat liver

An Approach to Pharmacological Targets of Pyrrole Family From Medicinal Chemistry Viewpoint

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