Candidate for anti-myotonic dystrophy drugs
A new hope for patients with muscular dystrophy
ChemPort.Ru based on the materials of the University of Illinois: New molecule heralds hope for muscular dystrophy treatmentFor patients suffering from myotonic dystrophy, there is a new hope.
A new low-molecular compound developed by researchers from the University of Illinois led by Roger Adams can destroy the protein-RNA clusters that cause this disease in living human cells.
The results of the study are an important first step in the development of a pharmaceutical treatment for a disease that is still considered incurable.
Myotonic dystrophy of the first type is the most common form of adult muscular dystrophy, which, for example, affects one person out of eight thousand in the United States. It manifests itself in progressive weakness, because as a result of this disease there is a gradual destruction of muscle tissue. There is currently no treatment for this disease, although some medical measures can alleviate some of the symptoms of the early stage of this dystrophy, the inevitable progress of degradation of muscle tissue cannot be stopped, therefore, the interest of pharmaceutical chemistry specialists in the search for drugs that can stop the disease is obvious.
Myotonic dystrophy of the first type is caused by a mutation of one gene. In a healthy person, one small fragment of this gene consists of cytosine-adenine-guanine (CAG) triplets repeated a small number of times, and in people affected by myotonic dystrophy of the first type, the CAG triplet can be repeated more than 50 times, in some cases up to a thousand. This excessive sequence is transcribed to RNA, as a result of which the improperly formed matrix RNA binds firmly to the MBNL1 protein, which plays an important role in regulating the protein balance of the cell, as a result of which MBNL1 is blocked in the cell nucleus as an aggregate.
Such aggregates are toxic to the cell. The fact is that the MNBL1 protein regulates the process of alternative splicing, which controls the amount of proteins produced by the cell. Cells containing MNBL1-RNA aggregates produce proteins in the wrong quantities, their relative content is unbalanced, and this imbalance affects more than 100 types of proteins vital to the cell.
Researchers from Illinois have synthesized a low-molecular compound with a polyamine chain that can penetrate into the cell nucleus, bind to the wrong RNA and force it to release the MBNL1 protein in such a way that it can work as part of its biochemical program. The size of the new compound is small, it dissolves in water and can pass through the cell membrane. It was precisely the possibility of penetration through the outer membrane of the cell and the membrane separating the nucleus from the cytoplasm of the cell that was the most difficult tasks that researchers had to solve, trying to use high-molecular compounds to destroy the cause of myotonic dystrophy. The new substance binds specifically only to the poly-GUT (guanine-uracil-cytosine) RNA site, without affecting other processes occurring in the cell.
Researchers have introduced a new compound into living cells with signs of myotonic dystrophy. Using microscopy methods, they were able to observe the response of cells to the introduction of a molecule into them. It was found that in just a few hours MNBL1-RNA clusters are destroyed, and the regulatory activity of the MNBL1 protein increases.
The Illinois researchers plan to collaborate with other groups of pharmacologists and test the effectiveness of the new compound on fruit flies and mice. Despite the fact that the resulting compound still has a large number of toxicity tests, the manifestation of side effects before clinical trials in humans, the discovery of a compound that can prevent one of the forms of muscular dystrophy at the cellular level is a significant step forward in the development of a drug against this ailment.
Article by Jahromi et al. A Novel CUG exp•MBNL1 Inhibitor with Therapeutic Potential for Myotonic Dystrophy Type 1 is published in the journal ACS Chemical Biology.
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