TY - JOUR
T1 - Synthesis and Biophysical Characterization of Fingolimod Derivatives as Cardiac Troponin Antagonists
AU - Kondacs, Laszlo
AU - Parijat, Priyanka
AU - Cobb, Alexander J. A.
AU - Kampourakis, Thomas
N1 - Funding Information:
We thank the British Heart Foundation for financial support (PG/19/52/34497 to T.K.) and James Jarvis, Sasi Conte, and Tam Bui from the King’s College London Centre of Biomolecular Spectroscopy for help and support.
Publisher Copyright:
© 2024 The Authors. Published by American Chemical Society.
PY - 2024/3/14
Y1 - 2024/3/14
N2 - Calcium binding to cardiac troponin C (cTnC) in the thin filaments acts as a trigger for cardiac muscle contraction. The N-lobe of cTnC (NcTnC) undergoes a conformational change in the presence of calcium that allows for interaction with the switch region of cardiac troponin I (cTnISP), releasing its inhibitory effect on the thin filament structure. The small molecule fingolimod inhibits cTnC–cTnISP interactions via electrostatic repulsion between its positively charged tail and positively charged residues in cTnISP and acts as a calcium desensitizer of the contractile myofilaments. Here we investigate the structure–activity relationship of the fingolimod hydrophobic headgroup and show that increasing the alkyl chain length increases both its affinity for NcTnC and its inhibitory effect on the NcTnC–cTnISP interaction and that decreasing flexibility completely abolishes these effects. Strikingly, the longer derivatives have no effect on the calcium affinity of cTnC, suggesting that they act as better inhibitors.
AB - Calcium binding to cardiac troponin C (cTnC) in the thin filaments acts as a trigger for cardiac muscle contraction. The N-lobe of cTnC (NcTnC) undergoes a conformational change in the presence of calcium that allows for interaction with the switch region of cardiac troponin I (cTnISP), releasing its inhibitory effect on the thin filament structure. The small molecule fingolimod inhibits cTnC–cTnISP interactions via electrostatic repulsion between its positively charged tail and positively charged residues in cTnISP and acts as a calcium desensitizer of the contractile myofilaments. Here we investigate the structure–activity relationship of the fingolimod hydrophobic headgroup and show that increasing the alkyl chain length increases both its affinity for NcTnC and its inhibitory effect on the NcTnC–cTnISP interaction and that decreasing flexibility completely abolishes these effects. Strikingly, the longer derivatives have no effect on the calcium affinity of cTnC, suggesting that they act as better inhibitors.
UR - http://www.scopus.com/inward/record.url?scp=85185253833&partnerID=8YFLogxK
U2 - 10.1021/acsmedchemlett.3c00511
DO - 10.1021/acsmedchemlett.3c00511
M3 - Article
SN - 1948-5875
VL - 15
SP - 413
EP - 417
JO - Acs Medicinal Chemistry Letters
JF - Acs Medicinal Chemistry Letters
IS - 3
ER -