Probing the mechanism of cardiovascular drugs using a covalent levosimendan analog

Sandra Elizabeth Pineda-Sanabria, Ian Michael Robertson, Yin-Biao Sun, Malcolm Irving, Brian D. Sykes

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)
157 Downloads (Pure)

Abstract

One approach to improve contraction in the failing heart is the administration of calcium (Ca2 +) sensitizers. Although it is known that levosimendan and other sensitizers bind to troponin C (cTnC), their in vivo mechanism is not fully understood. Based on levosimendan, we designed a covalent Ca2 + sensitizer (i9) that targets C84 of cTnC and exchanged this complex into cardiac muscle. The NMR structure of the covalent complex showed that i9 binds deep in the hydrophobic pocket of cTnC. Despite slightly reducing troponin I affinity, i9 enhanced the Ca2 + sensitivity of cardiac muscle. We conclude that i9 enhances Ca2 + sensitivity by stabilizing the open conformation of cTnC. These findings provide new insights into the in vivo mechanism of Ca2 + sensitization and demonstrate that directly targeting cTnC has significant potential in cardiovascular therapy.
Original languageEnglish
Pages (from-to)174-184
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume92
Early online date4 Feb 2016
DOIs
Publication statusPublished - Mar 2016

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