Molecules of the future. In Russia, they found a way to simplify the fight against cancer. How does he work?

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Molecules of the future. A way has been found in Russia to simplify the fight against cancer. How does he work?

One of the medical technologies of the future is aptamers – short DNA or RNA molecules that have many different uses, including the function of antibodies that fight pathogens. However, there are difficulties in obtaining aptamers for certain tasks – it is difficult to predict what shape a molecule should have in order to bind to the desired target. Russian scientists and their foreign colleagues have developed a new technique for modeling modified aptamers with a length shorter than that of their predecessors. “Lenta.ru” tells in detail about the study published in the prestigious scientific journal Molecular Therapy.

The world of nucleins

Nucleic acids, which include DNA and RNA, play one of the main roles in the functioning of any living being. They store information about the development of the organism, its physiology and evolution. They not only encode information about proteins, but also perform many important functions, including gene regulation. For example, short single-stranded RNAs easily form complex complexes, including ribozymes. Ribozymes are special RNA molecules that can have an enzymatic effect similar to proteins. That is why it is believed that it was ribozymes that could exist long before the emergence of the first living cell, catalyze their own reproduction and mutate in the process of chemical evolution, contributing to the emergence of life on Earth.

Thanks to advances in molecular biology and bionanotechnology, single-stranded DNA (ssDNA) has become a useful tool in medicine. Long ssDNAs are used to construct DNA origami – molecules of almost any shape that are suitable for creating new nanomaterials, computing devices, and even DNA computers. Short nucleic acids, also called oligonucleotides, are capable of mimicking antibodies – blood proteins that recognize and neutralize pathogens, including viruses and cancer cells. DNA analogs of antibodies refer to aptamers, that is, molecules capable of specifically binding to target molecules.

Aptamer was first obtained in December 2004, it was sodium pegaptanib, developed by Pfizer and Eyetech. For 20 years, aptamers have become widely used in medicine for targeted therapy – a method of fighting cancer, when drugs block the growth and spread of tumor cells by acting on specific molecules that are necessary for the development of a neoplasm. The specificity of aptamers makes them safe for healthy tissues, which do not secrete such compounds.

Molecules of the future. A way has been found in Russia to simplify the fight against cancer. How does he work?

The structure of an RNA aptamer specific to biotin. Image: Fdardel / Wikipedia

Currently, aptamers are produced by artificial evolution. The SELEX method consists in creating a large collection of oligonucleotides, consisting of random sequences. Oligonucleotides interact with the target substance, after which those that could not contact it are removed. This cycle repeats several times, and scientists select those molecules that have the greatest affinity for the desired compound. Differences in the properties of ssDNA are determined by their ability to fold into complex three-dimensional shapes. The molecular structure, in turn, depends on many factors, including temperature, acidity, and the presence of dissolved ions.

DNA constructor

Scientists from Moscow State University and the Krasnoyarsk Scientific Center, together with colleagues from Finland, Germany, Canada, Japan and the United States, have solved the difficult problem of optimizing an aptamer molecule for diagnosing cancer cells. Unlike its predecessor compound, the new sequence has 45 nucleotides less. This truncation made the functions of the aptamer optimal and made it possible to improve the binding of the molecule to tumor cells due to its greater specificity for specific target proteins.

2004

year

creation of the first aptamer – pegaptanib, which blocks vascular endothelial growth factor and is approved for use in the treatment of wet retinal macular degeneration

Designing an aptamer with a given molecular structure is a difficult task that requires powerful computers. Atomic-scale simulations can generate plausible molecular structures, but identifying the most likely ones requires enormous computational resources. This is due to the tiny energy difference between molecules of the same chemical composition, but with different molecular structures.

It is known that the LC-18 aptamer can bind to tumor cells of lung adenocarcinoma, tissues and blood plasma with high specificity. LC-18 is a sequence of 80 nucleotides, including two special regions of 20 nucleotides on each side – the primer. The primers serve as auxiliary functions by serving as a primer for the synthesis of a new oligonucleotide.

Molecules of the future. A way has been found in Russia to simplify the fight against cancer. How does he work?

Structure of the LC-18t aptamer and its predecessor. Image: Elsevier Inc.

There is a need to reduce the size of aptamers to improve binding properties and to reduce the cost of synthesis. The researchers have achieved the synthesis of a highly truncated 35 nucleotide LC-18 (LC-18t) that exhibits the same binding properties as its predecessor. The scientists then applied a number of theoretical methods, including DNA folding simulations, quantum chemical calculations, and computer simulations. The effectiveness of the aptamer has been tested in experiments on cancer cells.

First, it was tested whether the truncated aptamer is able to bind to cancer cells in the patient's body in the same way as the original LC-18. Experiments have demonstrated that LC-18t binds efficiently to stained lung tumor cells, but does not bind to healthy lungs and inflamed tissues. The reason for this was an increase in the binding energy of the molecule, and a decrease in length reduces the number of forms into which the molecule can be folded, which facilitates the process of molecular recognition of the target.

The future is modeling

The researchers also proposed a new protocol to model the structure of the aptamer in the future. This requires the use of small-angle X-ray scattering (SAXS), which is a powerful technique for observing the structural transitions of biological molecules in solutions similar to the environment inside a living organism. SAXS helps determine the shape of the aptamer in an experiment. This is followed by an initial molecular simulation using various computational methods, after which the data from the experiments and theoretical calculations are compared with each other.

Molecules of the future. A way has been found in Russia to simplify the fight against cancer. How does he work?

Various three-dimensional structures of the LC-18 aptamer. Image: Elsevier Inc.

The proposed procedure can also be used to analyze aptamer-target complexes in the future. Having obtained a reliable atomistic structure as a result of modeling, it is possible to rationalize the binding of the aptamer to a target, for example, a protein. This can be very useful in the development of new, more efficient aptamers based on data obtained from molecular modeling.

Aptamers with high target specificity and sensitivity, universal biophysical and pharmacokinetic properties, have taken a strong niche in the therapeutic drug market and have established themselves as a promising new class of drug compounds. It can be expected that, thanks to effective modeling methods, such compounds will become even more widespread and will become widely used in the fight against viral and bacterial infections, oncological diseases, and in the diagnosis of genetic and other disorders.

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