Conversion of a Cardiac Muscle Modulator from an Inhibitor to an Activator

TY - JOUR

T1 - Conversion of a Cardiac Muscle Modulator from an Inhibitor to an Activator

AU - Cai, Fangze

AU - Kampourakis, Thomas

AU - Parijat, Priyanka

AU - Cockburn, Kieran T.

AU - Sykes, Brian D.

N1 - Funding Information: This study was supported by grants from University of Alberta Faculty of Medicine Transitional Program (B.D.S.), Motyl Graduate Studentship (F.C.), and British Heart Foundation (Fellowship FS/16/3/31887 to T.K.). Publisher Copyright: © 2023 American Chemical Society.

PY - 2023/4/13

Y1 - 2023/4/13

N2 - The binding of calcium to cardiac troponin C (cTnC) enhances the binding of troponin I (cTnI) switch region to the regulatory domain of cTnC (cNTnC) and triggers muscle contraction. Several molecules alter the response of the sarcomere by targeting this interface; virtually all have an aromatic core that binds to the hydrophobic pocket of cNTnC and an aliphatic tail that interacts with the switch region of cTnI. W7 has been extensively studied, and the positively charged tail has been shown to be important for its inhibitory action. Herein we investigate the importance of the aromatic core of W7 by synthesizing compounds that have the core region of calcium activator dfbp-o with various lengths of the same tail (D-series). These compounds all bind more tightly to cNTnC-cTnI chimera (cChimera) than the analogous W-series compounds and show increased calcium sensitivity of force generation and ATPase activity, demonstrating that the cardiovascular system is tightly balanced.

AB - The binding of calcium to cardiac troponin C (cTnC) enhances the binding of troponin I (cTnI) switch region to the regulatory domain of cTnC (cNTnC) and triggers muscle contraction. Several molecules alter the response of the sarcomere by targeting this interface; virtually all have an aromatic core that binds to the hydrophobic pocket of cNTnC and an aliphatic tail that interacts with the switch region of cTnI. W7 has been extensively studied, and the positively charged tail has been shown to be important for its inhibitory action. Herein we investigate the importance of the aromatic core of W7 by synthesizing compounds that have the core region of calcium activator dfbp-o with various lengths of the same tail (D-series). These compounds all bind more tightly to cNTnC-cTnI chimera (cChimera) than the analogous W-series compounds and show increased calcium sensitivity of force generation and ATPase activity, demonstrating that the cardiovascular system is tightly balanced.

KW - Cardiac

KW - modulator

KW - sarcomere

KW - troponin

UR - http://www.scopus.com/inward/record.url?scp=85149475681&partnerID=8YFLogxK

U2 - 10.1021/acsmedchemlett.3c00033

DO - 10.1021/acsmedchemlett.3c00033

M3 - Article

AN - SCOPUS:85149475681

SN - 1948-5875

VL - 14

SP - 530

EP - 533

JO - Acs Medicinal Chemistry Letters

JF - Acs Medicinal Chemistry Letters

IS - 4

ER -