Drug discovery for heart failure targeting myosin-binding protein C

Bunch, Thomas A.; Guhathakurta, Piyali; Thompson, Andrew R.; Lepak, Victoria C.; Carter, Anna L.; Thomas, Jennifer J.; Thomas, David D.; Colson, Brett A.

doi:10.1016/j.jbc.2023.105369

Cited by 3 publications

(1 citation statement)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our study not only highlights the importance of phosphatases for regulating cMyBP-C phosphorylation, but also provides a useful framework for integrating data on cMyBP-C phosphorylation from cells or animals in future studies. Moreover, modulating cMyBP-C phosphorylation is increasingly considered a potentially promising therapeutic strategy 60 – 63 . An integrated and validated model of how cMyBP-C is regulated by both phosphatases and kinases could be used to design therapeutic strategies to optimize cMyBP-C phosphorylation in heart disease by modulating multiple rather than single enzymatic activities.…”

Section: Discussionmentioning

confidence: 99%

Cardiac myosin binding protein-C phosphorylation as a function of multiple protein kinase and phosphatase activities

Kampourakis,

Ponnam,

Campbell

et al. 2024

Nat Commun

View full text Add to dashboard Cite

Phosphorylation of cardiac myosin binding protein-C (cMyBP-C) is a determinant of cardiac myofilament function. Although cMyBP-C phosphorylation by various protein kinases has been extensively studied, the influence of protein phosphatases on cMyBP-C’s multiple phosphorylation sites has remained largely obscure. Here we provide a detailed biochemical characterization of cMyBP-C dephosphorylation by protein phosphatases 1 and 2 A (PP1 and PP2A), and develop an integrated kinetic model for cMyBP-C phosphorylation using data for both PP1, PP2A and various protein kinases known to phosphorylate cMyBP-C. We find strong site-specificity and a hierarchical mechanism for both phosphatases, proceeding in the opposite direction of sequential phosphorylation by potein kinase A. The model is consistent with published data from human patients and predicts complex non-linear cMyBP-C phosphorylation patterns that are validated experimentally. Our results suggest non-redundant roles for PP1 and PP2A under both physiological and heart failure conditions, and emphasize the importance of phosphatases for cMyBP-C regulation.

show abstract

Section: Discussionmentioning

confidence: 99%

Cardiac myosin binding protein-C phosphorylation as a function of multiple protein kinase and phosphatase activities

Kampourakis,

Ponnam,

Campbell

et al. 2024

Nat Commun

View full text Add to dashboard Cite

show abstract

Novel drug design and repurposing: An opportunity to improve translational research in cardiovascular diseases?

Rodríguez‐Zavala,

Zazueta

2024

Archiv der Pharmazie

View full text Add to dashboard Cite

Drug repurposing is defined as the use of approved therapeutic drugs for indications different from those for which they were originally designed. Repositioning diminishes both the time and cost for drug development by omitting the discovery stage, the analysis of absorption, distribution, metabolism, and excretion routes, as well as the studies of the biochemical and physiological effects of a new compound. Besides, drug repurposing takes advantage of the increased bioinformatics knowledge and availability of big data biology. There are many examples of drugs with repurposed indications evaluated in in vitro studies, and in pharmacological, preclinical, or retrospective clinical analyses. Here, we briefly review some of the experimental strategies and technical advances that may improve translational research in cardiovascular diseases. We also describe exhaustive research from basic science to clinical studies that culminated in the final approval of new drugs and provide examples of successful drug repurposing in the field of cardiology.

show abstract

Cardiac myosin-binding protein C N-terminal interactions with myosin and actin filaments: Opposite effects of phosphorylation and M-domain mutations

Wong,

Bunch,

Lepak

et al. 2024

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

Drug discovery for heart failure targeting myosin-binding protein C

Cited by 3 publications

References 35 publications

Cardiac myosin binding protein-C phosphorylation as a function of multiple protein kinase and phosphatase activities

Cardiac myosin binding protein-C phosphorylation as a function of multiple protein kinase and phosphatase activities

Novel drug design and repurposing: An opportunity to improve translational research in cardiovascular diseases?

Cardiac myosin-binding protein C N-terminal interactions with myosin and actin filaments: Opposite effects of phosphorylation and M-domain mutations

Contact Info

Product

Resources

About