Protein constructs: Malaria drug to help treat rare diseases
For the first time, scientists have established how the combined use of the antimalarial drug mefloquine and certain antibiotics restores protein biosynthesis in mutated cells. They conducted their research on mushrooms, but if the data is confirmed in the study of human material, it will be a breakthrough in the treatment of rare diseases. The data obtained will potentially allow the development of drugs necessary for patients who suffer from hereditary diseases, such as Duchenne muscular dystrophy (DMD). Experts called the study very promising. It opens up a new way to treat genetic diseases not by editing DNA, but by a milder intervention, affecting how the cell "reads" the existing code. For more information, see the Izvestia article.
How the body builds proteins
Scientists from Kazan (Volga Region) Federal University and colleagues investigated how the antimalarial drug mefloquine affects the functioning of cellular structures in the body responsible for protein assembly. As explained by experts, DNA is a molecule that stores information about the structure of all proteins in the body. And when a certain protein is synthesized in a cell, an RNA molecule is copied from a DNA fragment. The resulting sequence of nucleotides is read by the ribosome.
Authors of the article: Konstantin Usachev, Marat Yusupov, Shamil Validov
For each triple of nucleotides, the codon ribosome adds one amino acid, assembling them into a chain, which then folds into a protein. In this case, the first codon that reads the ribosome is called the start codon, and the last one, after which protein synthesis stops, is called the stop codon. In hereditary pathologies, such as Duchenne muscular dystrophy, associated with muscle degradation, a mutation occurs in DNA, as a result of which an extra stop codon appears at the beginning or in the middle of the RNA sequence. As a result, the ribosome traveling through the distorted RNA encounters it and prematurely stops protein synthesis. Because of this, it turns out to be unfinished.
To ensure that the ribosome does not stop and continues proper protein synthesis, aminoglycoside antibiotics can potentially be used. The authors of the study determined for the first time how the structure of ribosomes in fungal cells changes in the presence of the antimalarial drug mefloquine of these substances. To do this, the researchers used cryo—electron microscopy, a variant of electron microscopy in which samples are studied at low temperatures, as well as X—ray crystallography. This is a method that allows you to establish the three-dimensional structure of compounds by the way their crystals scatter X-rays.
The three-dimensional structure of the ribosome
It turned out that mefloquine causes the ribosome fragments to rotate relative to each other, thereby enhancing the effect of aminoglycosides, which allows the structure to continue protein synthesis.
— We have developed a new method for ribosome crystallization of Candida albicans yeast-like fungi, which allows us to see small molecules in the active centers of the ribosome, which was previously difficult to achieve using cryo-electron microscopy. By adding X-ray crystallography data to it, we were able to see in 3D with atomic resolution how the structure of the ribosome changes when binding to various molecules. My colleagues and I continue to study the structures of ribosomes from various organisms in order to better understand the basics of biochemical processes inside the cell," Konstantin Usachev, a participant in the project, Doctor of Physico—Mathematical Sciences, professor of the Department of Medical Physics at KFU, told Izvestia.
The data obtained will allow the development of drugs that interact with ribosomes and trigger further protein synthesis in the cells of patients who suffer from hereditary diseases associated with impaired protein synthesis.
The cure for Duchenne Muscular Dystrophy
Our body works thanks to proteins — they perform almost all functions in cells. But to create a protein, the cell needs to read the "recipe" from the DNA and assemble the molecule according to the instructions. This is done by a special cellular machine, the ribosome. It reads the code like an assembly line and assembles complex protein structures from amino acids. Without this work, there would be no muscles, no skin, no hormones, the expert of NTI "Helsnet", a biological scientist, founder of biomedtech startups BioAlg Corp. explained to Izvestia. and OncoUnite Dmitry Chebanov.
— Scientists have discovered that if the antimalarial drug mefloquine is added to aminoglycoside antibiotics, the ribosome can "step over" this error and continue assembly. That is, literally ignore the false stop signal and complete the complete protein. This is similar to a situation where a defective instruction in production tells you to stop working, but an experienced craftsman understands that this is a mistake and completes the product to the end. Previously, such an effect required large doses of antibiotics, which is harmful to the body," the scientist noted.
The research opens up a new way to treat genetic diseases not by editing DNA, but by a milder intervention, influencing how the cell "reads" the existing code. It is cheaper, easier and potentially safer, Dmitry Chebanov emphasized.
The study gives hope for the development of a new approach to the treatment of DMD and other hereditary diseases caused by premature stop codons, a geneticist, researcher at the Department of orphan Diseases and the Prevention of Disabling Diseases at the Research Institute of Pediatrics and Children's Health of the NCC No. 2 of the Russian National Research Medical University. academician B.V. Petrovsky" Veronika Popova.
— So far, it has been carried out on fungal cells, but if a similar effect is confirmed on human cells, this will open the way to clinical trials. Additional studies will be required on animal models of DMD (for example, mice with a mutation in the dystrophin gene). If further trials confirm the efficacy and safety of the combination of mefloquine and aminoglycosides, this may become a new treatment option not only for DMD, but also for other diseases caused by nonsense mutations. However, it will take at least 5-10 years to develop and implement such a drug," the specialist said.
Duchenne muscular dystrophy is a congenital, steadily progressive genetic disease that leads to loss of the ability to walk by the age of 10-12 and ends in death from cardiopulmonary failure in the third decade.
— About 1.3 thousand children with DMD have been diagnosed in Russia. Today, there are drugs in the world that can change the trajectory of the disease and significantly improve the quality and life expectancy of patients. This therapy is suitable for patients with certain mutations," the R-Pharm press service noted.
The results of the study, supported by a grant from the Russian Science Foundation (RSF), are published in the journal Proceedings of the National Academy of Sciences.
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