Modeling of S100A1ct interplay with SERCA2a transmembrane helices. Credit score: Circulation (2024). DOI: 10.1161/CIRCULATIONAHA.123.066961
Researchers from Heidelberg College, Heidelberg College Hospital (UKHD) and Heidelberg Institute for Theoretical Research (HITS) have developed an artificial peptide based mostly on the pure protein S100A1, an almost common “fuel” for weakened hearts.
The researchers mixed computer-aided strategies with lab research to research the therapeutic impact of the so-called S100A1ct peptide molecule. The outcomes have been revealed within the journal Circulation.
The protein S100A1 is produced within the coronary heart muscle cells and an vital controller of cardiac perform: it regulates the pumping motion of the center, stabilizes the center rhythm, ensures adequate power provide and successfully protects in opposition to maladaptive development, for instance after a coronary heart assault, that usually results in coronary heart muscle weak point and coronary heart failure.
For a future therapeutic use of this protein, scientists from the Heidelberg Medical School and the Schools for Engineering Sciences and Bioscience of Heidelberg College developed an artificial model of the protein by combining computer-based protein modeling and efficacy research on coronary heart muscle cells and animals.
This strategy led step-by-step to an optimized protein drug that might open up new therapy choices for acute cardiac insufficiency.
The analysis group led by Dr. Julia Ritterhoff and Professor Dr. Patrick Most, Head of the Molecular and Translational Cardiology Part within the Division of Cardiology, Angiology and Pneumology at UKHD, has been learning the S100A1 protein for greater than 20 years.
The crew has elucidated quite a few features of the protein within the cardiovascular system and, based mostly on this work, has already developed gene remedy strategies for the therapy of continual coronary heart failure. These approaches at the moment are being ready for scientific research by a start-up firm spun off from Heidelberg College and UKHD.
A part of the pure protein as an lively agent in opposition to acute coronary heart failure
Curiously, solely a particular part of the protein appears to be answerable for the therapeutic results of S100A1 in coronary heart muscle. “This molecular insight gave rise to the idea of only using the putative active part of the S100A1 protein as a therapeutic agent.” explains Dr. Ritterhoff.
This brief protein fragment, a so-called peptide, might be produced synthetically and immediately utilized intravenously as a drug with fast therapeutic efficacy. Such a medicinal idea with exact regulation of the center’s contractile perform through acceptable dosage could be conceivable, for instance, within the context of intensive medical therapy of decompensated acute coronary heart failure. In distinction, the gene remedy is directed in opposition to continual coronary heart failure.
The event of this translational structure-based drug design idea was solely made doable by the collaboration with the “Molecular and Cellular Modeling” group led by Professor Dr. Rebecca Wade at HITS and Heart of Molecular Biology of Heidelberg College (ZMBH). The strategy was to combine experiments on coronary heart muscle cells and animals and computational molecular modeling.
“Our lab developed a customized computer-aided modeling pipeline for this project to model the molecular structure of the peptide and interactions with the predicted molecular effectors in the diseased heart cells. The computational modeling guided the design of specific experiments to investigate the molecular mechanisms. In this way, the strengths of computer-aided modeling and the experimental expertise of the lab of Dr. Ritterhoff and Prof. Most complemented each other very effectively,” says Prof. Wade.
The peptide acts safely and therapeutically in clinically related preclinical fashions of coronary heart failure
Of their work, the 2 groups developed the essential construction of the brand new peptide, predicted its doable interactions with different proteins in coronary heart muscle cells. They used varied preclinical molecular, mobile and animal fashions to show that the brand new peptide therapeutic is protected and efficient to reverse coronary heart failure and that it even protects in opposition to deadly arrhythmias.
“The special thing about the molecular mechanism of S100A1ct is, that it increases cardiac function of the weakened heart and at the same time protects against arrhythmias. The drugs currently available, which are used for acute decompensated heart failure treatment in intensive care, temporarily increase cardiac output but can have profound negative effects on the heart rhythm and worsen the prognosis of our patients,” explains Prof. Most.
“We therefore consider the S100A1ct peptide to be a real advance and particularly suitable for intravenous administration in the event of an acute drop in cardiac function, which can occur following a severe heart attack or myocarditis, for example.” Earlier than it may be used within the clinic, nonetheless, preclinical growth and security assessments must be carried out.
Extra data:
Dorothea Kehr et al, S100A1ct: A Artificial Peptide Derived From S100A1 Protein Improves Cardiac Efficiency and Survival in Preclinical Coronary heart Failure Fashions, Circulation (2024). DOI: 10.1161/CIRCULATIONAHA.123.066961
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Therapeutic designer peptide to fight acute coronary heart muscle weak point (2025, February 12)
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