Dilated cardiomyopathy (DICA) is a group of disorders characterized by constitutionally weak heart muscles, with the vast majority of cases believed to be genetic. DICA often causes life-threatening complications as the heart struggles to pump blood. According to the American Heart Association, it is most likely to affect children and adults under 50. The body’s natural response to a weak heart is to force it to compensate to ensure blood flow to every part of the body. In a large subset of patients, DICA is associated with at least one of hundreds of different genetic mutations, offering potential targets for precision treatments tailored to the individual. A research team co-led by scientists at the University of Arizona College of Medicine in Tucson has discovered that an osteoporosis drug could counteract a rare genetic mutation underlying this type of heart disease.
Pharmaceutical companies are unlikely to develop a specific drug because there must be enough patients with the mutation to make it feasible. Unfortunately, some of these mutations are very, very rare, perhaps even affecting a handful of patients. Since pharmaceutical companies are unlikely to invest money in research investigating genetic conditions that affect so few people, leader Dr. Hesham Sadek has taken another approach: drug repurposing, using drugs approved by the official pharmacopoeia. A mutation can knock that protein out of shape and render it unable to function properly in that engine. By pushing the mutant protein back into shape with a small molecule, the structure can be corrected. The team focused on K210del, the first mutation discovered associated with DICA, to investigate how its defective shape prevents the heart from functioning properly.
Sadek’s team was the first to create a 3D model of K210del and compare it to its healthy counterpart to identify where it is misshapen and how it interacts with surrounding proteins to slow its function. K210del induced an allosteric shift in the troponin complex, distorting the calcium-binding activation domain of troponin C (TnnC), resulting in disorganization of calcium ions. Next, using a supercomputer and artificial intelligence, they screened 2,000 approved drugs to see if any could bind to the misshapen protein and restore it to its correct position. The top five or six drugs were all used for osteoporosis. After further testing in cell cultures and animal models, they refined their results. Only one of the six drugs, risedronate, corrected the protein’s shape to normal. Dr. Sadek said that while cancer and cystic fibrosis researchers have taken a similar approach, this is the first time “structure correction” has been applied to heart disease.
- Edited by Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
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