An FDA-approved drug structurally and phenotypically corrects the K210del mutation in genetic cardiomyopathy models
Ping Wang, … , Sakthivel Sadayappan, Hesham A. Sadek
Ping Wang, … , Sakthivel Sadayappan, Hesham A. Sadek
Published February 17, 2025
Citation Information: J Clin Invest. 2025;135(4):e174081. https://doi.org/10.1172/JCI174081.
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An FDA-approved drug structurally and phenotypically corrects the K210del mutation in genetic cardiomyopathy models

Abstract

Dilated cardiomyopathy (DCM) due to genetic disorders results in decreased myocardial contractility, leading to high morbidity and mortality rates. There are several therapeutic challenges in treating DCM, including poor understanding of the underlying mechanism of impaired myocardial contractility and the difficulty of developing targeted therapies to reverse mutation-specific pathologies. In this report, we focused on K210del, a DCM-causing mutation, due to 3-nucleotide deletion of sarcomeric troponin T (TnnT), resulting in loss of Lysine210. We resolved the crystal structure of the troponin complex carrying the K210del mutation. K210del induced an allosteric shift in the troponin complex resulting in distortion of activation Ca2+-binding domain of troponin C (TnnC) at S69, resulting in calcium discoordination. Next, we adopted a structure-based drug repurposing approach to identify bisphosphonate risedronate as a potential structural corrector for the mutant troponin complex. Cocrystallization of risedronate with the mutant troponin complex restored the normal configuration of S69 and calcium coordination. Risedronate normalized force generation in K210del patient-induced pluripotent stem cell–derived (iPSC-derived) cardiomyocytes and improved calcium sensitivity in skinned papillary muscles isolated from K210del mice. Systemic administration of risedronate to K210del mice normalized left ventricular ejection fraction. Collectively, these results identify the structural basis for decreased calcium sensitivity in K210del and highlight structural and phenotypic correction as a potential therapeutic strategy in genetic cardiomyopathies.

Authors

Ping Wang, Mahmoud Salama Ahmed, Ngoc Uyen Nhi Nguyen, Ivan Menendez-Montes, Ching-Cheng Hsu, Ayman B. Farag, Suwannee Thet, Nicholas T. Lam, Janaka P. Wansapura, Eric Crossley, Ning Ma, Shane Rui Zhao, Tiejun Zhang, Sachio Morimoto, Rohit Singh, Waleed Elhelaly, Tara C. Tassin, Alisson C. Cardoso, Noelle S. Williams, Hayley L. Pointer, David A. Elliott, James W. McNamara, Kevin I. Watt, Enzo R. Porrello, Sakthivel Sadayappan, Hesham A. Sadek

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Figure 2

Structure correction of ΔK210 complex by risedronate.

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Structure correction of ΔK210 complex by risedronate. (A) Schematic flow...
(A) Schematic flow chart for the in silico molecular virtual screening, starting with energy minimized FDA-approved small molecules to be followed by semiflexible docking study targeting the hinge region in ΔK210 complex to end up with the top 5 drug candidates. (B) Chemgauss scores for bisphosphonates family members: zoledronic, risedronic, pamidronic, alendronic, and ibandronic acids. (C) Surface representation colored by the vacuum electrostatic potential of ΔK210 complex. The hinge region is highlighted in black box and risedronate is docked into the hinge region. (D) Representation of the overall structure of ΔK210 complex in the presence of risedronate. (E) Representation showing superimposition of WT (gray), ΔK210 (cyan), and ΔK210 complex in the presence of risedronate (purple). (F) Surface representation colored by the vacuum electrostatic potential of ΔK210 complex in the presence of risedronate. (G) Highlight of the hinge region of TnnT and TnnI showing superimposition of WT (gray), ΔK210 (cyan), and ΔK210 complex in the presence of risedronate (purple). Specific residues in the hinge region are shown in stick representation. (H) Detailed interaction of Ca2+ in the activation Ca2+-binding pocket for TnnC in ΔK210 complex in the presence of risedronate. Specific residues coordinating the Ca2+are shown in green stick representation. Hydrogen bonds are indicated with black dashed lines. (I) Representation showing superimposition of the detailed interaction of Ca2+ in the activation Ca2+-binding pocket for TnnC in ΔK210 complex (cyan) and ΔK210 complex in the presence of risedronate (green). (J and K) Fluorescence-based measurement of the binding affinity of Ca2+ to WT- and ΔK210-troponin complexes in the absence and presence of risedronate. Significance was assessed through Tukey’s multiple-comparison tests. *P < 0.05; ****P < 0.0001.