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- Getting into proteins: "guardians of the genome" reprogram the body to fight tumors
Getting into proteins: "guardians of the genome" reprogram the body to fight tumors
Scientists from Russia and the UK have created molecules that restore the antitumor activity of a protein called the molecular guardian of the genome. It stops the division of damaged cells and triggers their apoptosis — controlled cell death. Experts speak about the huge prospects of the research. If these molecules reach real drugs, doctors will receive a point tool that not only hits the tumor, but also fixes the root of the problem. However, for now, scientists are only taking the first steps, and further preclinical and clinical studies are needed, experts told Izvestia.
What are the guardian molecules of the genome?
Scientists at Kazan (Volga Region) Federal University have developed new molecules that restore the antitumor function of the molecular "guardian of the genome" protein p53, the press service of the Ministry of Education and Science told Izvestia. The compound got its name for its ability to stop the division of damaged cells and trigger their apoptosis — controlled cell death. However, half of all tumors have mutations in the gene encoding p53, which deprive the protein of its protective function and allow cells to divide uncontrollably.
The researchers' special attention was attracted by the Y220C mutation, which disrupts the three-dimensional structure of p53 and forms a hydrophobic "pocket" in its molecule. This mutation occurs in more than 100,000 new cancers annually, including liver, breast, and lung tumors, and is one of the most common structural mutations of p53.
Using a structurally targeted screening of the compound library, the KFU researchers, together with their British colleagues, discovered and synthesized three new derivatives of indazole (a nitrogen-containing aromatic compound). Two of them showed selective activity against tumor cells with the Y220C mutation: they contributed to the "switching" of the protein to a normal conformation and the restoration of expression of its target genes responsible for triggering apoptosis. This effect was accompanied by increased tumor cell death, whereas no such changes were observed in cells with normal p53.
— This protein decides the fate of the cell: in case of severe DNA damage, it triggers self-destruction, preventing it from turning into a tumor. When p53 mutates, the cells lose this control. We are looking for ways to restore the mutant forms to their normal structure and function. In our work, we have discovered new chemical frameworks that act as chaperone-like compounds. They help the defective protein to fold properly and reactivate the antitumor genes. Such compounds become the starting point for the development of new—generation drugs aimed at the selective restoration of p53 functions," says Rania Khadiullina, the first author of the study, senior researcher at the Institute of Biomedical Technologies of KFU.
According to scientists, the obtained compounds act mildly, without pronounced toxic effects, and at the same time selectively trigger apoptosis in cells with the p53-Y220C mutation. This opens up the prospect of creating a new class of targeted anticancer drugs aimed at the molecular causes of the disease.
"It was important for us to show that small changes in the chemical structure of a molecule can fundamentally affect its ability to "switch" a mutant protein," said Emil Bulatov, a leading researcher at the Institute of Biomedical Technologies and the Institute of Industrial Biopharmaceuticals of the Institute of Fundamental Medicine and Biology of KFU, commenting on the development.
Prospects of the "guardians of the genome" in oncomedicine
The development of KFU is an attempt to bring the inactive "guardian of the genome" p53 back to life. This protein is a real lock that has been keeping the gates of cancer mutations closed for many years, molecular biologist Arina Kholkina told Izvestia.
— With the Y220C mutation, a gap appears in his armor, and the cellular order begins to crumble. The new indazole derivatives work like molecular tailors: they carefully "stitch" this gap and help the protein regain its working shape. P53 seems to remember its responsibilities and triggers an alarm when a cell goes astray and becomes cancerous. Therefore, the prospects are huge. Restoring the function of p53 is an old dream of oncology. If these molecules reach real drugs, doctors will receive a point tool that does not just hit the tumor, but fixes the root of the problem," the expert said.
When this mechanism is triggered, cells begin to follow the safety rules laid down from birth again, and this opens up a completely different horizon for future therapies, Arina Kholkina noted.
The development of drugs that trigger the self—destruction of tumor cells that have a specific mutation is a promising strategy, said Mikhail Bolkov, a researcher at the Institute for the Study of Aging at the Russian National Research Medical Center of the Russian National Research Medical University.
"This molecule can become a fairly universal drug against various types of tumors if damage to the p53 protein is involved in their development. However, scientists still have a long way to go: the compound must prove its effectiveness both in animal trials and in clinical tests," he noted.
The results of the work, done in collaboration with the laboratory of Professor Matthias Baude from the University of Southampton in the UK, are published in an article in the journal Cell Death Discovery. The research was carried out with the support of the Russian Science Foundation and a grant allocated to Kazan Federal University as part of a state assignment in the field of scientific activity.
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