Determining mechanistic effects of therapeutic compounds aimed at treatment of heart failure

Heart failure is a life-threatening clinical syndrome with a poor overall prognosis and is a leading cause of hospitalization of older adults. The heartbeat depends critically on carefully regulated flows of calcium in the heart muscle cells. Heart failure is commonly associated with disturbances in the transport of calcium back to the sarcoplasmic reticulum (SR) storage after heart muscle contraction. This transport is carried out by ATP-dependent Ca2+-transporting proteins (SERCA) embedded in the SR membranes. A few SERCA-activating compounds have been developed, but suffer from lack of specificity. A major hurdle that prevents implementing activators in clinical usage, is that drug development currently is blind to the underlying molecular mechanism (including the transport kinetics) of SERCA activation. Therefore, we will use time-resolved X-ray solution scattering to determine which parts of the reaction cycle are affected by the drug and the associated time scales.