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
  • 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: [email protected].
  • 10. University of Ljubljana, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia. Electronic address: [email protected].
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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