JRP/2019/836/RyRinHeart

RyRinHeart – Discovery of Ryanodine Receptor Inhibitors for Heart Diseases

Principal Investigator: Alexandra Zahradníková

Duration: January 2020 – December 2022
Coordinating Organization: Institute of Experimental Endocrinology, BRC SAV, Bratislava

Annotation:

Cardiac ryanodine receptors (RyR2) control the pumping function of the heart by regulating calcium release required for cardiac myocyte contraction. Many heart diseases are accompanied by disorders of calcium release. These disorders could be suppressed by drugs that prevent unwanted RyR2 activity. The aim of this project is to develop specific inhibitors, adapted to the structure of cardiac RyR2, with the potential to treat calcium handling disorders in heart disease.
We will use our original knowledge of the structure of RyR2 to identify loci in the 3D-structure of RyR2 that reduce its activity by ligand binding. This will allow us to design and synthesize RyR2 inhibitors. We will test their efficacy in experiments monitoring RyR activity. The in situ efficacy of selected agents, most promising for regulation of RyR2 function, will be tested on isolated cardiac myocytes and finally on the hearts of healthy animals and animals with heart disease.
Methodologically, the project is based on two pillars: molecular structure simulations, molecular dynamics, and computer-assisted drug design, the main body of expertise being the Turkish side, and a wide range of experimental and theoretical methods of studying ion channel function and calcium signalling (biochemical and electrophysiological methods, confocal microscopy, mathematical modelling of dynamics of intracellular processes), where expertise will be provided by the Slovak side.
The project aims to contribute to the solution of a serious medical problem using advanced technologies, original expertise and new approaches developed in collaborating laboratories.

Keywords:

ryanodíne receptor, cardiac myocyte, calcium signalling, drug design and testing, molecular modelling, mathematical modelling, cardiac diseases

Objectives:

The overall aim of the project is to design a RyR2 inhibitor potentially suitable for prevention of arrhythmias in diseased heart. To achieve this goal we formulated the following specific objectives:

using biochemical and biophysical methods, to increase understanding of the mechanism of RyR2 inhibition by known inhibitors
using molecular modelling and computer-aided drug design to search for novel drugs, and using biochemical and biophysical methods to test compounds that optimize the use of RyR2 inhibitory mechanisms for preventing unwanted calcium release in cardiac myocytes
to test the most promising compound in an in vivo model of cardiac disease in mice

Publications:

	Baglaeva I, Iaparov B, Zahradnik I, Zahradnikova A (2023). Analysis of noisy transient signals based on Gaussian process regression. Biophys J 122: 451–459. doi: 10.1016/j.bpj.2023.01.003.
	Iaparov B, Baglaeva I, Zahradnik I, Zahradnikova A (2022). Magnesium ions moderate calcium-induced calcium release in cardiac calcium release sites by binding to ryanodine receptor activation and inhibition sites. Front Physiol 12: 805956. doi: 10.3389/fphys.2021.805956.
	Iaparov B, Zahradnik I, Moskvin AS, Zahradnikova A (2021): In silico simulations reveal that RYR distribution affects the dynamics of calcium release in cardiac myocytes. J Gen Physiol 153: e202012685 doi: 10.1085/jgp.202012685.
	Iaparov B, Zahradnik I, Moskvin AS, Zahradnikova A (2020): Synergy of calcium release site determinants in control of calcium release events in cardiac myocytes. bioRXiv : doi: https://doi.org/10.1101/2020.08.26.260968.
	Zahradnikova A, Iaparov B, Zahradnik I (2020): The problem of accuracy in single-channel open probability measurements. Prog Biophys Mol Biol 157: 94-106 doi: 10.1016/j.pbiomolbio.2020.05.002.