From cancer and autoimmune diseases
Molecular design helped in the creation of a prototype of a personalized medicine from scorpion venom
RNF Press Service
Russian scientists, with the participation of colleagues from Belgium, artificially changed the specificity of one of the components of scorpion venom that can block potassium channels.
Mottled scorpion Mesobuthus eupeus.
The resulting substance, unlike natural, interacts mainly with channels that are responsible for the development of autoimmune diseases and cancer. The development is a prototype of a personalized medicine. The work was supported by a grant from the Presidential Research Projects Program of the Russian Science Foundation (RNF). The results of the study are published in the journal Frontiers in Pharmacology (Gigolaev et al., Tuning Scorpion Toxin Selectivity: Switching From KV1.1 to KV1.3).
A computer-generated model of a potassium channel complex and a modified blocker from the venom of the scorpion Mesobuthus eupeus in the cell membrane. Source: Gigolaev et al.
Potassium channels – the "gate" for potassium ions in the cell membrane – are vital for any cell. They are involved in almost all cellular processes: conducting nerve impulses, cell division and their interaction with each other, as well as the immune response. At the same time, in different tissues of the body there are different types (isoforms) of potassium channels that help the cell to function properly.
The activity of potassium channels can be stopped by special substances or blocking ligands, which causes cells to lose their functions or work incorrectly. This is used by poisonous organisms to protect themselves or immobilize prey, however, their poisons can also be used as medicines. So, they can protect against autoimmune diseases – prevent immune cells from attacking healthy human cells – or slow down the spread and growth of tumors.
"Our global goal is to understand how the interaction sites of peptide ligands and potassium channels are arranged," comments Alexey Kuzmenkov, Head of the RNF grant project, Doctor of Chemical Sciences, Researcher at the Laboratory of Molecular Instruments for Neurobiology Institute of Bioorganic Chemistry named after M.M. Shemyakin and Yu.A. Ovchinnikov (IBH) of the Russian Academy of Sciences. – This will help to find the key to the creation of a new generation of drugs for personalized medicine."
In their work, scientists from IBH RAS (Moscow, Russia) and the University of Leuven (Belgium) studied blockers of a special isoform of the potassium channel (Kv1.3), which is involved in autoimmune processes, and is also necessary for the growth of malignant tumors. One of the components of the venom of the mottled scorpion Mesobuthus eupeus (MeKTx13-3) was chosen as a "molecular framework" for creating a specific blocker. This molecule is a folded chain of several amino acids, or a polypeptide, capable of clogging potassium channels like a cork.
First, the authors simulated the interaction of the blocker with channels on a computer. It turned out that some amino acids can be replaced in the polypeptide molecule so that the blocker loses the ability to bind to other isoforms of potassium channels, with the exception of the selected Kv1.3. Next, the scientists obtained an altered polypeptide in the synthesis system based on E. coli and studied its ability to block potassium current through the membrane. As predicted by computer modeling, the new derivative showed a hundredfold increase in specificity to Kv1.3 compared to its natural counterpart.
"We have developed a new approach to the design of polypeptide ligands based on computer calculations. In the article, we are just conducting such a design and "turning" a molecule that initially acted better on Kv1.1 into a Kv1.3-selective ligand," explains Alexey Kuzmenkov.
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