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

Lopez, Ludivine; Waard, Stephan De; Meudal, Hervé; Caumes, Cécile; Khakh, Kuldip; Peigneur, Steve; Oliveira-Mendes, Bárbara Bruna Ribeiro; Lin, Sophia; Waele, Jolien De; Montnach, Jérôme; Cestèle, Sandrine; Tessier, Agnès; Johnson, J. P.; Mantegazza, Massimo; Tytgat, Jan; Cohen, Charles J.; Béroud, Rémy; Bosmans, Frank; Landon, C.; Waard, Michel De

doi:10.1016/j.biopha.2023.115173

Cited by 3 publications

(1 citation statement)

References 52 publications

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“…The venom of the Chinese tarantula Chilobrachys guangxiensis contains a family of peptides named Jingzhaotoxins (JzTx). The JzTx-34 is a 35-residue polypeptide (Table 4) that inhibits Na v 1.7 channels, exhibiting antinociceptive properties with higher affinity as compared to all other subtypes of Na v [62]. This toxin also inhibits voltage-gated potassium channels (K v ) in rat dorsal root ganglion (DRG) neurons.…”

Section: Peptides Derived From Spidersmentioning

confidence: 99%

Analgesic Peptides: From Natural Diversity to Rational Design

Gach-Janczak,

Biernat,

Kuczer

et al. 2024

Molecules

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Pain affects one-third of the global population and is a significant public health issue. The use of opioid drugs, which are the strongest painkillers, is associated with several side effects, such as tolerance, addiction, overdose, and even death. An increasing demand for novel, safer analgesic agents is a driving force for exploring natural sources of bioactive peptides with antinociceptive activity. Since the G protein-coupled receptors (GPCRs) play a crucial role in pain modulation, the discovery of new peptide ligands for GPCRs is a significant challenge for novel drug development. The aim of this review is to present peptides of human and animal origin with antinociceptive potential and to show the possibilities of their modification, as well as the design of novel structures. The study presents the current knowledge on structure-activity relationship in the design of peptide-based biomimetic compounds, the modification strategies directed at increasing the antinociceptive activity, and improvement of metabolic stability and pharmacodynamic profile. The procedures employed in prolonged drug delivery of emerging compounds are also discussed. The work summarizes the conditions leading to the development of potential morphine replacements.

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Section: Peptides Derived From Spidersmentioning

confidence: 99%

Analgesic Peptides: From Natural Diversity to Rational Design

Gach-Janczak,

Biernat,

Kuczer

et al. 2024

Molecules

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Spider and scorpion knottins targeting voltage-gated sodium ion channels in pain signaling

Wang,

Luo,

Peng

et al. 2024

Biochemical Pharmacology

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The contribution of Na_V1.6 to the efficacy of voltage‐gated sodium channel inhibitors in wild type and Na_V1.6 gain‐of‐function (GOF) mouse seizure control

Johnson,

Focken,

Karimi Tari

et al. 2024

British J Pharmacology

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Background and PurposeInhibitors of voltage‐gated sodium channels (NaVs) are important anti‐epileptic drugs, but the contribution of specific channel isoforms is unknown since available inhibitors are non‐selective. We aimed to create novel, isoform selective inhibitors of Nav channels as a means of informing the development of improved antiseizure drugs.Experimental ApproachWe created a series of compounds with diverse selectivity profiles enabling block of NaV1.6 alone or together with NaV1.2. These novel NaV inhibitors were evaluated for their ability to inhibit electrically evoked seizures in mice with a heterozygous gain‐of‐function mutation (N1768D/+) in Scn8a (encoding NaV1.6) and in wild‐type mice.Key ResultsPharmacologic inhibition of NaV1.6 in Scn8aN1768D/+ mice prevented seizures evoked by a 6‐Hz shock. Inhibitors were also effective in a direct current maximal electroshock seizure assay in wild‐type mice. NaV1.6 inhibition correlated with efficacy in both models, even without inhibition of other CNS NaV isoforms.Conclusions and ImplicationsOur data suggest NaV1.6 inhibition is a driver of efficacy for NaV inhibitor anti‐seizure medicines. Sparing the NaV1.1 channels of inhibitory interneurons did not compromise efficacy. Selective NaV1.6 inhibitors may provide targeted therapies for human Scn8a developmental and epileptic encephalopathies and improved treatments for idiopathic epilepsies.

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

Cited by 3 publications

References 52 publications

Analgesic Peptides: From Natural Diversity to Rational Design

Analgesic Peptides: From Natural Diversity to Rational Design

Spider and scorpion knottins targeting voltage-gated sodium ion channels in pain signaling

The contribution of Na_V1.6 to the efficacy of voltage‐gated sodium channel inhibitors in wild type and Na_V1.6 gain‐of‐function (GOF) mouse seizure control

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

Cited by 3 publications

References 52 publications

Analgesic Peptides: From Natural Diversity to Rational Design

Analgesic Peptides: From Natural Diversity to Rational Design

Spider and scorpion knottins targeting voltage-gated sodium ion channels in pain signaling

The contribution of NaV1.6 to the efficacy of voltage‐gated sodium channel inhibitors in wild type and NaV1.6 gain‐of‐function (GOF) mouse seizure control

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The contribution of Na_V1.6 to the efficacy of voltage‐gated sodium channel inhibitors in wild type and Na_V1.6 gain‐of‐function (GOF) mouse seizure control