TY  - JOUR
AU  - Hendrickx, Louise Antonia
AU  - Dobričić, Vladimir
AU  - Toplak, Žan
AU  - Peigneur, Steve
AU  - Peterlin Mašič, Lucija
AU  - Tomašič, Tihomir
AU  - Tytgat, Jan
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3568
AB  - The voltage-gated potassium channel Kv1.3 is involved in multiple autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, diabetes mellitus type 1 and psoriasis. In many auto-immune diseases better treatment options are desired as existing therapies are often ineffective or become less effective over time, for which Kv1.3 inhibitors arise as promising candidates. In this study, five compounds were selected based on a 3D similarity searching methodology and subsequently screened ex vivo on the Kv1.3 channel. The screening resulted in two compounds inhibiting the Kv1.3 channel, of which TVS-12 was the most potent compound, while TVS-06 -although less potent- showed an excellent selectivity for Kv1.3. For both compounds the mechanism of action was investigated by an electrophysiological characterization on the Kv1.3 channel and three Kv1.3 mutants, designed to resemble the pore region of Kv1.2 channels. Structurally, the presence of a benzene ring and/or an oxane ring seems to cause a better interaction with the Kv1.3 channel, resulting in a 20-fold higher potency for TVS-12.
PB  - Elsevier
T2  - Bioorganic Chemistry
T1  - Design and characterization of a novel structural class of Kv1.3 inhibitors
VL  - 98
DO  - 10.1016/j.bioorg.2020.103746
ER  - 

@article{
author = "Hendrickx, Louise Antonia and Dobričić, Vladimir and Toplak, Žan and Peigneur, Steve and Peterlin Mašič, Lucija and Tomašič, Tihomir and Tytgat, Jan",
year = "2020",
abstract = "The voltage-gated potassium channel Kv1.3 is involved in multiple autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, diabetes mellitus type 1 and psoriasis. In many auto-immune diseases better treatment options are desired as existing therapies are often ineffective or become less effective over time, for which Kv1.3 inhibitors arise as promising candidates. In this study, five compounds were selected based on a 3D similarity searching methodology and subsequently screened ex vivo on the Kv1.3 channel. The screening resulted in two compounds inhibiting the Kv1.3 channel, of which TVS-12 was the most potent compound, while TVS-06 -although less potent- showed an excellent selectivity for Kv1.3. For both compounds the mechanism of action was investigated by an electrophysiological characterization on the Kv1.3 channel and three Kv1.3 mutants, designed to resemble the pore region of Kv1.2 channels. Structurally, the presence of a benzene ring and/or an oxane ring seems to cause a better interaction with the Kv1.3 channel, resulting in a 20-fold higher potency for TVS-12.",
publisher = "Elsevier",
journal = "Bioorganic Chemistry",
title = "Design and characterization of a novel structural class of Kv1.3 inhibitors",
volume = "98",
doi = "10.1016/j.bioorg.2020.103746"
}

Hendrickx, L. A., Dobričić, V., Toplak, Ž., Peigneur, S., Peterlin Mašič, L., Tomašič, T.,& Tytgat, J.. (2020). Design and characterization of a novel structural class of Kv1.3 inhibitors. in Bioorganic Chemistry
Elsevier., 98.
https://doi.org/10.1016/j.bioorg.2020.103746

Hendrickx LA, Dobričić V, Toplak Ž, Peigneur S, Peterlin Mašič L, Tomašič T, Tytgat J. Design and characterization of a novel structural class of Kv1.3 inhibitors. in Bioorganic Chemistry. 2020;98.
doi:10.1016/j.bioorg.2020.103746 .

Hendrickx, Louise Antonia, Dobričić, Vladimir, Toplak, Žan, Peigneur, Steve, Peterlin Mašič, Lucija, Tomašič, Tihomir, Tytgat, Jan, "Design and characterization of a novel structural class of Kv1.3 inhibitors" in Bioorganic Chemistry, 98 (2020),
https://doi.org/10.1016/j.bioorg.2020.103746 . .