title: Probing the mechanism of cardiovascular drugs using a covalent levosimendan analog.
abstract: One approach to improve contraction in the failing heart is the administration of calcium (Ca(2+)) 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 Ca(2+) 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 Ca(2+) sensitivity of cardiac muscle. We conclude that i9 enhances Ca(2+) sensitivity by stabilizing the open conformation of cTnC. These findings provide new insights into the in vivo mechanism of Ca(2+) sensitization and demonstrate that directly targeting cTnC has significant potential in cardiovascular therapy.
authors: Department of Biochemistry, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
authors: Sandra E
authors: SE
authors: Pineda-Sanabria
authors: Randall Division of Cell and Molecular Biophysics and British Heart Foundation Centre of Research Excellence, New Hunt's House, Guy's Campus, King's College London, London SE1 1UL, UK.
authors: Ian M
authors: IM
authors: Robertson
authors: Randall Division of Cell and Molecular Biophysics and British Heart Foundation Centre of Research Excellence, New Hunt's House, Guy's Campus, King's College London, London SE1 1UL, UK.
authors: Yin-Biao
authors: YB
authors: Sun
authors: Randall Division of Cell and Molecular Biophysics and British Heart Foundation Centre of Research Excellence, New Hunt's House, Guy's Campus, King's College London, London SE1 1UL, UK.
authors: Malcolm
authors: M
authors: Irving
authors: Department of Biochemistry, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada. Electronic address: brian.sykes@ualberta.ca.
authors: Brian D
authors: BD
authors: Sykes
mesh_terms: D000818:Animals; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D002317:Cardiovascular Agents / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D006333:Heart Failure / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D006835:Hydrazones / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D009200:Myocardial Contraction / Q000187:drug effects; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects; D011724:Pyridazines / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D051381:Rats; D000077464:Simendan; D019209:Troponin C / Q000737:chemistry* / Q000378:metabolism; D019210:Troponin I / Q000737:chemistry / Q000378:metabolism
chemical_list: D002317:Cardiovascular Agents; D006835:Hydrazones; D011724:Pyridazines; D019209:Troponin C; D019210:Troponin I; D000077464:Simendan; D002118:Calcium
keywords: Calcium sensitizer; Covalent modulator; Heart failure; Levosimendan; Troponin C