Structure-function studies of sponge-derived compounds on the cardiac CaV3.1 channel

Depuydt, Anne-Sophie (author), Patel, Piyush A. (author), Toplak, Žan (author), Bhat, Chinmaya (author), Voráčová, Manuela (author), Eteläinen, Irene (author), Vitulano, Fiammetta (author), Hribernik, Nives (author), Tomašič, Tihomir (author), Peterlin-Mašič, Lucija (author)

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 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 CaV3.1 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 CaV3.1 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 CaV3.1 channel. A selectivity screening showed that these analogs are also active on hERG channels. Collectively, a new class of CaV3 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 CaV channels.

• Language: English
• Keywords: T-type calcium channels, ion channels, purpurealidin I, bromotyrosines, marine-derived bioactive compounds
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2023
• Number of pages: 15 str.
• Numbering: Vol. 24, iss. 4, art. 3429
• PID: 20.500.12556/RUL-144330
• UDC: 577.352:615.4:54
• ISSN on article: 1422-0067
• DOI: 10.3390/ijms24043429
• COBISS.SI-ID: 141468419
• Publication date in RUL: 15.02.2023

Record is a part of a journal

• Title: International journal of molecular sciences
• Shortened title: Int. j. mol. sci.
• Publisher: MDPI
• ISSN: 1422-0067
• COBISS.SI-ID: 2779162

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: T-tip kalcijevih kanalčkov, purpurealidin I, bromotirozini, bioaktivne spojine morskega izvora, farmacevtska kemija, ionski kanalčki