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Structure-Function Studies of Sponge-Derived Compounds on the Cardiac Ca_V3.1 Channel.

ABSTRACT: T-type calcium (Ca_V3) channels are involved in cardiac automaticity, development, and excitation-contraction coupling in normal cardiac myocytes. Their functional role becomes more pronounced in the process of pathological cardiac hypertrophy and heart failure. Currently, no Ca_V3 channel inhibitors are used in clinical settings. To identify novel T-type calcium channel ligands, purpurealidin analogs were electrophysiologically investigated. These compounds are alkaloids produced as secondary metabolites by marine sponges, and they exhibit a broad range of biological activities. In this study, we identified the inhibitory effect of purpurealidin I (1) on the rat Ca_V3.1 channel and conducted structure-activity relationship studies by characterizing the interaction of 119 purpurealidin analogs. Next, the mechanism of action of the four most potent analogs was investigated. Analogs 74, 76, 79, and 99 showed a potent inhibition on the Ca_V3.1 channel with IC₅₀'s at approximately 3 μM. No shift of the activation curve could be observed, suggesting that these compounds act like a pore blocker obstructing the ion flow by binding in the pore region of the Ca_V3.1 channel. A selectivity screening showed that these analogs are also active on hERG channels. Collectively, a new class of Ca_V3 channel inhibitors has been discovered and the structure-function studies provide new insights into the synthetic design of drugs and the mechanism of interaction with T-type Ca_V channels.

SUBMITTER: Depuydt AS

PROVIDER: S-EPMC9962600 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Structure-Function Studies of Sponge-Derived Compounds on the Cardiac CaV3.1 Channel.

Depuydt Anne-Sophie AS Patel Piyush A PA Toplak Žan Ž Bhat Chinmaya C Voráčová Manuela M Eteläinen Irene I Vitulano Fiammetta F Bruun Tanja T Lempinen Antti A Hribernik Nives N Mäki-Lohiluoma Eero E Hendrickx Louise L Pinheiro-Junior Ernesto Lopes EL Tomašič Tihomir T Mašič Lucija Peterlin LP Yli-Kauhaluoma Jari J Kiuru Paula P Tytgat Jan J Peigneur Steve S

International journal of molecular sciences 20230208 4

T-type calcium (CaV3) channels are involved in cardiac automaticity, development, and excitation-contraction coupling in normal cardiac myocytes. Their functional role becomes more pronounced in the process of pathological cardiac hypertrophy and heart failure. Currently, no CaV3 channel inhibitors are used in clinical settings. To identify novel T-type calcium channel ligands, purpurealidin analogs were electrophysiologically investigated. These compounds are alkaloids pro ...[more]

PMID: 36834837

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Project description:Background/Objectives: The Ca2+-activated K+ channel KCa3.1 is not only involved in physiological processes such as immune reactions and control of vascular tone, but is highly expressed in various tumor entities. Thus, imaging of KCa3.1 channels comes into focus for the localization of high channel density, i.e., for tumor diagnosis. In particular, the physicochemical properties of the fluorescent probes should be improved compared to existing probes. Methods: The small molecule inhibitor of the KCa3.1 channel, senicapoc, was used as a warhead and was coupled with different fluorescent dyes. After synthesis of the novel probes, their physicochemical properties (lipophilicity, photophysical properties) and their ability to image KCa3.1 channels in A549-3R lung tumor cells were determined. Results: In order to increase the polarity and quantum yield of reported fluorescent probes, three strategies were followed: (1) An F-atom at the B-atom of bodipy-labeled senicapoc derivatives 9a, 9b, and 15a was replaced by a OCH3 moiety, which decreased the logP value by one log-unit. (2) The p-phenylene moiety of the linker was replaced by an aliphatic tetramethylene linker decreasing the lipophilicity by 0.3-0.5 log-units. (3) Instead of bodipy dyes, fluorescein was coupled with the senicapoc warhead resulting in very polar probes 21a and 21b with low logP values of 1.5 and 1.3, respectively. Introduction of an ethyl moiety at the bodipy core increased the quantum yield, which resulted in the best punctate staining pattern of fixed and living A549-3R lung tumor cells with the ethylbodipy-labeled senicapoc derivative 10b. The specificity was shown by various control experiments. Co-staining with 10b and an antibody did not result in overlapping signals. Conclusions: The well-balanced lipophilicity and fluorescent quantum yield render the ethylbodipy-labeled senicapoc derivative 10b a very good probe to image selectively KCa3.1 ion channels in fixed and living tumor cells. It was hypothesized that the antibody binds selectively at the closed channel (58.5%), whereas the senicapoc-bodipy conjugate 10b binds selectively at the open channel (41.5%). The ratio 58.5:41.5 reflects the ratio of the ion channel in closed and open conformations.

Dataset Information

Structure-Function Studies of Sponge-Derived Compounds on the Cardiac Ca_V3.1 Channel.

Publications

Structure-Function Studies of Sponge-Derived Compounds on the Cardiac Ca<sub>V</sub>3.1 Channel.

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