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

doi:10.1016/j.yjmcc.2016.02.003

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

University of Alberta

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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 language	English
Pages (from-to)	174-184
Number of pages	11
Journal	Journal of Molecular and Cellular Cardiology
Volume	92
Early online date	4 Feb 2016
DOIs	https://doi.org/10.1016/j.yjmcc.2016.02.003
Publication status	Published - Mar 2016

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Probing the mechanism of cardiovascular_PINEDA-SANABRIA_Accepted2February2016_GOLD VoRFinal published version, 1.4 MBLicence: CC BY

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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 (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.",

author = "{Elizabeth Pineda-Sanabria}, Sandra and Robertson, {Ian Michael} and Yin-Biao Sun and Malcolm Irving and Sykes, {Brian D.}",

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T1 - Probing the mechanism of cardiovascular drugs using a covalent levosimendan analog

AU - Elizabeth Pineda-Sanabria, Sandra

AU - Robertson, Ian Michael

AU - Sun, Yin-Biao

AU - Irving, Malcolm

AU - Sykes, Brian D.

PY - 2016/3

Y1 - 2016/3

N2 - 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.

AB - 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.

U2 - 10.1016/j.yjmcc.2016.02.003

DO - 10.1016/j.yjmcc.2016.02.003

M3 - Article

SN - 0022-2828

VL - 92

SP - 174

EP - 184

JO - Journal of Molecular and Cellular Cardiology

JF - Journal of Molecular and Cellular Cardiology

ER -

Probing the mechanism of cardiovascular drugs using a covalent levosimendan analog

Abstract

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