2. Academic Validation
  3. Immunosuppressive effects of new thiophene-based KV1.3 inhibitors

Immunosuppressive effects of new thiophene-based KV1.3 inhibitors

  • Eur J Med Chem. 2023 Jun 25;259:115561. doi: 10.1016/j.ejmech.2023.115561.
Špela Gubič 1,  Alberto Montalbano 2,  Cesare Sala 2,  Andrea Becchetti 3,  Louise Antonia Hendrickx 4,  Kenny M Van Theemsche 5,  Ernesto Lopes Pinheiro-Junior 4,  Ginevra Chioccioli Altadonna 6,  Steve Peigneur 4,  Janez Ilaš 1,  Alain J Labro 7,  Luis A Pardo 8,  Jan Tytgat 4,  Tihomir Tomašič 1,  Annarosa Arcangeli 9,  Lucija Peterlin Mašič 10
Affiliations

Affiliations

  • 1 University of Ljubljana, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia.
  • 2 University of Florence, Department of Experimental and Clinical Medicine, I-50134, Florence, Italy.
  • 3 University of Milano-Bicocca, Department of Biotechnology and Biosciences, Piazza della Scienza 2, I-20126, Milano, Italy.
  • 4 University of Leuven, Toxicology and Pharmacology, Campus Gasthuisberg, Onderwijs en Navorsing 2, Herestraat 49, PO Box 922, 3000, Leuven, Belgium.
  • 5 University of Antwerp, Department of Biomedical Sciences, Campus Drie Eiken, Universiteisplein 1, 2610, Wilrijk, Belgium; Ghent University, Department of Basic and Applied Medical Sciences, Corneel Heymanslaan 10, 9000, Ghent, Belgium.
  • 6 University of Siena, Department of Medical Biotechnologies, I-53100, Siena, Italy.
  • 7 Ghent University, Department of Basic and Applied Medical Sciences, Corneel Heymanslaan 10, 9000, Ghent, Belgium.
  • 8 Max-Planck Institute for Experimental Medicine, AG Oncophysiology, Hermann-Rein-Str. 3, 37075, Göttingen, Germany.
  • 9 University of Florence, Department of Experimental and Clinical Medicine, I-50134, Florence, Italy. Electronic address: annarosa.arcangeli@unifi.it.
  • 10 University of Ljubljana, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia. Electronic address: lucija.peterlinmasic@ffa.uni-lj.si.
PMID: 37454520 DOI: 10.1016/j.ejmech.2023.115561
Abstract

Voltage-gated Potassium Channel KV1.3 inhibitors have been shown to be effective in preventing T-cell proliferation and activation by affecting intracellular Ca2+ homeostasis. Here, we present the structure-activity relationship, KV1.3 inhibition, and immunosuppressive effects of new thiophene-based KV1.3 inhibitors with nanomolar potency on K+ current in T-lymphocytes and KV1.3 inhibition on Ltk- cells. The new KV1.3 inhibitor trans-18 inhibited KV1.3 -mediated current in phytohemagglutinin (PHA)-activated T-lymphocytes with an IC50 value of 26.1 nM and in mammalian Ltk- cells with an IC50 value of 230 nM. The KV1.3 inhibitor trans-18 also had nanomolar potency against KV1.3 in Xenopus laevis oocytes (IC50 = 136 nM). The novel thiophene-based KV1.3 inhibitors impaired intracellular Ca2+ signaling as well as T-cell activation, proliferation, and colony formation.

Keywords

Immunosuppressive; Ion channel; K(V)1.3 inhibitor; T-lymphocyte.

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