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Innovative Drugs Targeting Ion Channels
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Innovative Drugs Targeting Ion Channels

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 3930

Special Issue Editor

Dr. Sergey Kozlov

E-Mail Website
Guest Editor
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia
Interests: the bioinformatic approaches development for transcriptomes analysis and in proteomics of invertebrate venoms; innovative targeted drugs

Special Issue Information

Dear Colleagues,

The Special Issue should be formulated as a description of current molecular approaches for cell tuning via ion channels activity modulating. Ion channels are important molecules that control the membrane potential in a normal cell, and their excessive or insufficient functionality can lead to pathology development and carcinogenesis. First of all, ion channel functions are associated with neuron activity and network support, which touch neurodegenerative and neurological diseases, but the involvement of ion channels in the functional regulation of almost all potent processes in vertebrates has been demonstrated. In this regard, it is interesting to collect different materials in one issue with regard to the involvement of some ion channels in pathological processes, together with a ligand-based methodology used for resolving such problems in the future. Of particular interest are therapeutic approaches based on genetic manipulations to regulate the representation of ion channels on membrane, results on animal models, classical biochemical and biophysical results, and molecular imaging methodology development (utilizing ligands to ion channels). As well as the topics mentioned above, other experimental articles and reviews dealing with ion channels and their modulators are welcome.

Dr. Sergey Kozlov
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • channelopathies
  • ion channels regulation
  • ligand-receptor interaction
  • drug design
  • selective targeting
  • diagnostic tools

Published Papers (3 papers)

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Research

15 pages, 5380 KiB  
Article
Opioid Analgesic as a Positive Allosteric Modulator of Acid-Sensing Ion Channels
by Dmitry I. Osmakov, Lyudmila V. Onoprienko, Aleksandr P. Kalinovskii, Sergey G. Koshelev, Vasiliy N. Stepanenko, Yaroslav A. Andreev and Sergey A. Kozlov
Int. J. Mol. Sci. 2024, 25(3), 1413; https://doi.org/10.3390/ijms25031413 - 24 Jan 2024
Viewed by 759
Abstract
Tafalgin (Taf) is a tetrapeptide opioid used in clinical practice in Russia as an analgesic drug for subcutaneous administration as a solution (4 mg/mL; concentration of 9 mM). We found that the acid-sensing ion channels (ASICs) are another molecular target for this molecule. [...] Read more.
Tafalgin (Taf) is a tetrapeptide opioid used in clinical practice in Russia as an analgesic drug for subcutaneous administration as a solution (4 mg/mL; concentration of 9 mM). We found that the acid-sensing ion channels (ASICs) are another molecular target for this molecule. ASICs are proton-gated sodium channels that mediate nociception in the peripheral nervous system and contribute to fear and learning in the central nervous system. Using electrophysiological methods, we demonstrated that Taf could increase the integral current through heterologically expressed ASIC with half-maximal effective concentration values of 0.09 mM and 0.3 mM for rat and human ASIC3, respectively, and 1 mM for ASIC1a. The molecular mechanism of Taf action was shown to be binding to the channel in the resting state and slowing down the rate of desensitization. Taf did not compete for binding sites with both protons and ASIC3 antagonists, such as APETx2 and amiloride (Ami). Moreover, Taf and Ami together caused an unusual synergistic effect, which was manifested itself as the development of a pronounced second desensitizing component. Thus, the ability of Taf to act as a positive allosteric modulator of these channels could potentially cause promiscuous effects in clinical practice. This fact must be considered in patients’ treatment. Full article
(This article belongs to the Special Issue Innovative Drugs Targeting Ion Channels)
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20 pages, 3773 KiB  
Article
Tetracyclic 1,4-Naphthoquinone Thioglucoside Conjugate U-556 Blocks the Purinergic P2X7 Receptor in Macrophages and Exhibits Anti-Inflammatory Activity In Vivo
by Sergei Kozlovskiy, Evgeny Pislyagin, Ekaterina Menchinskaya, Ekaterina Chingizova, Leonid Kaluzhskiy, Alexis S. Ivanov, Galina Likhatskaya, Irina Agafonova, Yuri Sabutski, Sergey Polonik, Igor Manzhulo and Dmitry Aminin
Int. J. Mol. Sci. 2023, 24(15), 12370; https://doi.org/10.3390/ijms241512370 - 2 Aug 2023
Cited by 1 | Viewed by 991
Abstract
P2X7 receptors (P2X7Rs) are ligand-gated ion channels that play a significant role in inflammation and are considered a potential therapeutic target for some inflammatory diseases. We have previously shown that a number of synthetic 1,4-naphthoquinones are capable of blocking P2X7Rs in neuronal and [...] Read more.
P2X7 receptors (P2X7Rs) are ligand-gated ion channels that play a significant role in inflammation and are considered a potential therapeutic target for some inflammatory diseases. We have previously shown that a number of synthetic 1,4-naphthoquinones are capable of blocking P2X7Rs in neuronal and macrophage cells. In the present investigation, we have demonstrated the ability of the tetracyclic quinone-thioglucoside conjugate U-556, derived from 1,4-naphthoquinone thioglucoside, to inhibit ATP-induced Ca2+ influx and YO-PRO-1 dye uptake, which indicates blocking P2X7R in RAW 264.7 macrophages. This process was accompanied by the inhibition of ATP-induced reactive oxygen species production in macrophages, as well as the macrophage survival strengthening under ATP toxic effects. Nevertheless, U-556 had no noticeable antioxidant capacity. Naphthoquinone-thioglucoside conjugate U-556 binding to the extracellular part of the P2X7R was confirmed by SPR analysis, and the kinetic characteristics of this complex formation were established. Computer modeling predicted that U-556 binds the P2X7R allosteric binding site, topographically similar to that of the specific A438079 blocker. The study of biological activity in in vivo experiments shows that tetracylic conjugate significantly reduces inflammation provoked by carrageenan. The data obtained points out that the observed physiological effects of U-556 may be due to its ability to block the functioning of the P2X7R. Full article
(This article belongs to the Special Issue Innovative Drugs Targeting Ion Channels)
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16 pages, 3615 KiB  
Article
Inhibitory Effects of Nobiletin on Voltage-Gated Na+ Channel in Rat Ventricular Myocytes Based on Electrophysiological Analysis and Molecular Docking Method
by Youwei Gu, Jieru Wang, Mengting Li, Fei Zhong, Jie Xiang and Zhengxin Xu
Int. J. Mol. Sci. 2022, 23(23), 15175; https://doi.org/10.3390/ijms232315175 - 2 Dec 2022
Viewed by 1763
Abstract
Nobiletin (NOB) has attracted much attention owing to its outstanding bioactivities. This study aimed to investigate its anti-arrhythmic effect through electrophysiological and molecular docking studies. We assessed the anti-arrhythmic effects of NOB using aconitine-induced ventricular arrhythmia in a rat model and the electrophysiological [...] Read more.
Nobiletin (NOB) has attracted much attention owing to its outstanding bioactivities. This study aimed to investigate its anti-arrhythmic effect through electrophysiological and molecular docking studies. We assessed the anti-arrhythmic effects of NOB using aconitine-induced ventricular arrhythmia in a rat model and the electrophysiological effects of NOB on rat cardiomyocytes utilizing whole-cell patch-clamp techniques. Moreover, we investigated the binding characters of NOB with rNav1.5, rNav1.5/QQQ, and hNaV1.5 via docking analysis, comparing them with amiodarone and aconitine. NOB pretreatment delayed susceptibility to ventricular premature and ventricular tachycardia and decreased the incidence of fatal ventricular fibrillation. Whole-cell patch-clamp assays demonstrated that the peak current density of the voltage-gated Na+ channel current was reversibly reduced by NOB in a concentration-dependent manner. The steady-state activation and recovery curves were shifted in the positive direction along the voltage axis, and the steady-state inactivation curve was shifted in the negative direction along the voltage axis, as shown by gating kinetics. The molecular docking study showed NOB formed a π-π stacking interaction with rNav1.5 and rNav1.5/QQQ upon Phe-1762, which is the homolog to Phe-1760 in hNaV1.5 and plays an important role in antiarrhythmic action This study reveals that NOB may act as a class I sodium channel anti-arrhythmia agent. Full article
(This article belongs to the Special Issue Innovative Drugs Targeting Ion Channels)
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