Immunosuppressive effects of new thiophene-based KV1.3 inhibitors

Špela Gubič; Alberto Montalbano; Cesare Sala; Andrea Becchetti; Louise Antonia Hendrickx; Kenny M Van Theemsche; Ernesto Lopes Pinheiro-Junior; Ginevra Chioccioli Altadonna; Steve Peigneur; Janez Ilaš; Alain J Labro; Luis A Pardo; Jan Tytgat; Tihomir Tomašič; Annarosa Arcangeli; Lucija Peterlin Mašič

doi:10.1016/j.ejmech.2023.115561

Immunosuppressive effects of new thiophene-based K_V1.3 inhibitors

Eur J Med Chem. 2023 Nov 5:259:115561. doi: 10.1016/j.ejmech.2023.115561. Epub 2023 Jun 25.

Authors

Špela Gubič¹, Alberto Montalbano², Cesare Sala², Andrea Becchetti³, Louise Antonia Hendrickx⁴, Kenny M Van Theemsche⁵, Ernesto Lopes Pinheiro-Junior⁴, Ginevra Chioccioli Altadonna⁶, Steve Peigneur⁴, Janez Ilaš¹, Alain J Labro⁷, Luis A Pardo⁸, Jan Tytgat⁴, Tihomir Tomašič¹, Annarosa Arcangeli⁹, Lucija Peterlin Mašič¹⁰

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 K_V1.3 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, K_V1.3 inhibition, and immunosuppressive effects of new thiophene-based K_V1.3 inhibitors with nanomolar potency on K⁺ current in T-lymphocytes and K_V1.3 inhibition on Ltk^- cells. The new K_V1.3 inhibitor trans-18 inhibited K_V1.3 -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 K_V1.3 inhibitor trans-18 also had nanomolar potency against K_V1.3 in Xenopus laevis oocytes (IC₅₀ = 136 nM). The novel thiophene-based K_V1.3 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.

MeSH terms

Animals
Immunosuppressive Agents* / chemistry
Mammals / metabolism
Potassium Channel Blockers / pharmacology
Potassium Channels / metabolism
Potassium Channels / pharmacology
Potassium Channels, Voltage-Gated* / pharmacology
Structure-Activity Relationship
T-Lymphocytes
Thiophenes* / chemistry
Thiophenes* / pharmacology

Substances

Potassium Channel Blockers
Potassium Channels
Potassium Channels, Voltage-Gated
Thiophenes
Immunosuppressive Agents