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Design and characterization of a novel structural class of Kv1.3 inhibitors.
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2020-03-18 , DOI: 10.1016/j.bioorg.2020.103746 Louise Antonia Hendrickx 1 , Vladimir Dobričić 2 , Žan Toplak 3 , Steve Peigneur 1 , Lucija Peterlin Mašič 3 , Tihomir Tomašič 3 , Jan Tytgat 1
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2020-03-18 , DOI: 10.1016/j.bioorg.2020.103746 Louise Antonia Hendrickx 1 , Vladimir Dobričić 2 , Žan Toplak 3 , Steve Peigneur 1 , Lucija Peterlin Mašič 3 , Tihomir Tomašič 3 , Jan Tytgat 1
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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.
中文翻译：
一种新型结构的Kv1.3抑制剂的设计和表征。
电压门控钾通道Kv1.3涉及多种自身免疫性疾病，例如多发性硬化症，类风湿性关节炎，1型糖尿病和牛皮癣。在许多自身免疫性疾病中，人们希望有更好的治疗选择，因为随着时间的流逝，现有疗法通常无效或变得无效，为此，Kv1.3抑制剂应运而生。在这项研究中，基于3D相似性搜索方法选择了5种化合物，随后在Kv1.3通道上进行了离体筛选。筛选导致两种化合物抑制Kv1.3通道，其中TVS-12是最有效的化合物，而TVS-06（尽管效力较低）显示出对Kv1.3的出色选择性。对于这两种化合物，通过在Kv1上进行电生理学表征来研究其作用机理。3个通道和3个Kv1.3突变体，旨在类似于Kv1.2通道的孔区域。从结构上讲，苯环和/或恶烷环的存在似乎会导致与Kv1.3通道更好的相互作用，从而使TVS-12的效力提高20倍。
更新日期：2020-03-19
中文翻译：
一种新型结构的Kv1.3抑制剂的设计和表征。
电压门控钾通道Kv1.3涉及多种自身免疫性疾病，例如多发性硬化症，类风湿性关节炎，1型糖尿病和牛皮癣。在许多自身免疫性疾病中，人们希望有更好的治疗选择，因为随着时间的流逝，现有疗法通常无效或变得无效，为此，Kv1.3抑制剂应运而生。在这项研究中，基于3D相似性搜索方法选择了5种化合物，随后在Kv1.3通道上进行了离体筛选。筛选导致两种化合物抑制Kv1.3通道，其中TVS-12是最有效的化合物，而TVS-06（尽管效力较低）显示出对Kv1.3的出色选择性。对于这两种化合物，通过在Kv1上进行电生理学表征来研究其作用机理。3个通道和3个Kv1.3突变体，旨在类似于Kv1.2通道的孔区域。从结构上讲，苯环和/或恶烷环的存在似乎会导致与Kv1.3通道更好的相互作用，从而使TVS-12的效力提高20倍。
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