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Novel Blocker of Onco SK3 Channels Derived from Scorpion Toxin Tamapin and Active against Migration of Cancer Cells.

ABSTRACT: Peptide-based therapy against cancer is a field of great interest for biomedical developments. Since it was shown that SK3 channels promote cancer cell migration and metastatic development, we started using these channels as targets for the development of antimetastatic drugs. Particularly, tamapin (a peptide found in the venom of the scorpion Mesobuthus tamulus) is the most specific toxin against the SK2 channel currently known. Considering this fact, we designed diverse tamapin mutants based on three different hypotheses to discover a new potent molecule to block SK3 channels. We performed in vitro studies to evaluate this new toxin derivative inhibitor of cancer cell migration. Our results can be used to generate a new tamapin-based therapy against cancer cells that express SK3 channels.

SUBMITTER: Mayorga-Flores M

PROVIDER: S-EPMC7429966 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Novel Blocker of Onco SK3 Channels Derived from Scorpion Toxin Tamapin and Active against Migration of Cancer Cells.

Mayorga-Flores Marlen M Chantôme Aurélie A Melchor-Meneses Carolina Monserrath CM Domingo Isabelle I Titaux-Delgado Gustavo Alfredo GA Galindo-Murillo Rodrigo R Vandier Christophe C Del Río-Portilla Federico F

ACS medicinal chemistry letters 20200710 8

Peptide-based therapy against cancer is a field of great interest for biomedical developments. Since it was shown that SK3 channels promote cancer cell migration and metastatic development, we started using these channels as targets for the development of antimetastatic drugs. Particularly, tamapin (a peptide found in the venom of the scorpion <i>Mesobuthus tamulus</i>) is the most specific toxin against the SK2 channel currently known. Considering this fact, we designed diverse tamapin mutants ...[more]

PMID: 32832033

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Project description:Scorpion β-toxin 4 from Centruroides suffusus suffusus (Css4) enhances the activation of voltage-gated sodium channels through a voltage sensor trapping mechanism by binding the activated state of the voltage sensor in domain II and stabilizing it in its activated conformation. Here we describe the antagonist and partial agonist properties of a mutant derivative of this toxin. Substitution of seven different amino acid residues for Glu(15) in Css4 yielded toxin derivatives with both increased and decreased affinities for binding to neurotoxin receptor site 4 on sodium channels. Css4(E15R) is unique among this set of mutants in that it retained nearly normal binding affinity but lost its functional activity for modification of sodium channel gating in our standard electrophysiological assay for voltage sensor trapping. More detailed analysis of the functional effects of Css4(E15R) revealed weak voltage sensor trapping activity, which was very rapidly reversed upon repolarization and therefore was not observed in our standard assay of toxin effects. This partial agonist activity of Css4(E15R) is observed clearly in voltage sensor trapping assays with brief (5 ms) repolarization between the conditioning prepulse and the test pulse. The effects of Css4(E15R) are fit well by a three-step model of toxin action involving concentration-dependent toxin binding to its receptor site followed by depolarization-dependent activation of the voltage sensor and subsequent voltage sensor trapping. Because it is a partial agonist with much reduced efficacy for voltage sensor trapping, Css4(E15R) can antagonize the effects of wild-type Css4 on sodium channel activation and can prevent paralysis by Css4 when injected into mice. Our results define the first partial agonist and antagonist activities for scorpion toxins and open new avenues of research toward better understanding of the structure-function relationships for toxin action on sodium channel voltage sensors and toward potential toxin-based therapeutics to prevent lethality from scorpion envenomation.

Dataset Information

Novel Blocker of Onco SK3 Channels Derived from Scorpion Toxin Tamapin and Active against Migration of Cancer Cells.

Publications

Novel Blocker of Onco SK3 Channels Derived from Scorpion Toxin Tamapin and Active against Migration of Cancer Cells.

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