The first day of the scientific session of the General Meeting of the Siberian Branch of the Russian Academy was devoted to one of the biggest challenges facing humanity today - the fight against coronavirus infection. Doctors and biologists, chemists and specialists in mathematical modeling spoke about the contribution of scientific and educational organizations of Siberia to overcoming the pandemic.

It is difficult to overestimate the contribution of biological institutes and companies of the Novosibirsk Scientific Center to solving priority problems during the pandemic. Novosibirsk biotechnologists were faced with the task of developing direct-acting antiviral drugs and creating vaccines. “Biosan — Biolabmix fully provided Russian enterprises with key components for PCR test systems,” said Academician Valentin Viktorovich Vlasov, Chairman of the Joint Scientific Council of the Siberian Branch of the Russian Academy of Sciences for Biological Sciences. — The leaders in the production of mass test systems were the companies Vector-Best JSC and Medico-Biological Union LLC, which produced more than 50 million test materials during the pandemic. This is 22% of all those produced in Russia. In addition, employees of the Institute of Chemical Biology and Fundamental Medicine of the Siberian Branch of the Russian Academy of Sciences created a test system that allows analysis in 35 minutes. Much has been done in the highly promising areas of synthetic biology, and the development of RNA vaccines and direct-acting antiviral drugs has begun. For example, the head of the immunogenetics laboratory at the Institute of Molecular and Cellular Biology of the Siberian Branch of the Russian Academy of Sciences, Doctor of Biological Sciences Alexander Vladimirovich Taranin and his colleagues have developed a high-tech and effective method for producing monoclonal antibodies."

Despite the active work to combat the virus and its consequences, according to the academician, the Russian Federation lags behind leading countries in the most important areas of molecular biology and biotechnology. "Our universities need to create adequate conditions for training specialists in these extremely promising research areas. In addition, we need to improve effective diagnostic and therapeutic tools for infectious diseases, as well as form an instrument base - this is a priority area for many years. At the same time, we should develop principles for deploying a network of laboratories and medical institutions in the event of epidemic threats," Valentin Vlasov noted.

Academician Vladimir Aleksandrovich Kozlov, Director of the Research Institute of Fundamental and Clinical Immunology, drew attention to the immunological component of solutions to the COVID-19 problem. “Any infection is tied to the interaction of the pathogen with the immune system, on which the outcome will depend. Therefore, already at the first stages of clinical manifestations of the disease, it is necessary to assess the presence of certain indicators of immune activity that allow predicting the development of severe complications. And of course, the issue of assessing individual sensitivity to the vaccine in different people, taking into account the dose of the administered antigen and the frequency of administration, should be acute. No less important is non-specific prevention, that is, all kinds of effects on the immune system to increase its functional activity: drugs, dietary supplements, moderate physical activity, diet, hardening,” said Academician Kozlov.

The scientist recalled that the COVID-19 virus has a mechanism for escaping from the action of immune system cells, which allows it to multiply in the body against the background of weakened immunity. In connection with this feature, molecular cellular immunotherapy should become the basis for treating coronavirus disease, according to Vladimir Kozlov.

The search for and study of the mechanisms of action of new compounds with activity against COVID-19 continues at the N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry of the Siberian Branch of the Russian Academy of Sciences and the V. Zelman Institute of Medicine and Psychology of the Novosibirsk State University.

“Since 2013, the molecular pathology laboratory has been using a pseudotyping system in its research. When a cell is infected with two types of virus at the same time, hybrid variants may appear, where the core and envelope proteins are from different viruses. We have created a technology that allows us to re-dress the surface protein of the virus. Such hybrid particles can be used to study the interaction of surface proteins of any viruses with receptors. We have already used this system to search for bird flu and filoviruses such as Ebola and Marburg,” explained Corresponding Member of the Russian Academy of Sciences Andrei Georgievich Pokrovsky.

Based on the developed method, with the emergence of COVID-19, employees of the NIOC SB RAS obtained a pseudovirus that contains the surface S-protein of SARS-CoV-2. This made it possible to find compounds that block the entry of the virus into target cells. The researchers found that the penetration of the coronavirus into the cell can be prevented by a derivative of betulinic acid. Betulin and ursolic acid are currently being studied for their antiviral activity against SARS-CoV-2.

Head of the Laboratory of Physiology, Molecular and Clinical Pharmacology of the E. D. Goldberg Research Institute of Pharmacology and Regenerative Medicine of the Tomsk Scientific Research Medical Center of the Russian Academy of Sciences, Corresponding Member of the Russian Academy of Sciences Vladimir Vasilyevich Udut spoke about new technologies developed by Siberian scientists that help to stop and correct lung damage caused by COVID-19.

“Ultimately, all tissues of the body die from hypoxia: ventilation, when oxygen does not enter the blood, or circulatory, when the blood cannot carry it,” the scientist explained. “In severe, acute conditions, the phenomenon of ventilation, or respiratory, failure occurs, which is largely associated with the development of depression, anxiety, sleep disorders, weakness, shortness of breath and other unpleasant post-COVID symptoms.”

Tomsk scientists have developed an effective technology that helps people who have had COVID-19 to recover. It consists of the following: post-COVID patients are given xenon-oxygen inhalations, which give an extremely quick positive reaction. The identified phenomenon of rapid (the course of treatment was five days) restoration of the airiness of the lung tissue raised a number of questions for scientists: if the consumption of xenon in the inhalation mixture increases, then where is it spent, which lung tissue substrate acts as its acceptor, and what is the mechanism of lung pneumatization during Xe-O2 inhalations? As a result of an experiment on a model of viral pneumonitis, specialists found out that the target of xenon is pulmonary surfactant (a mixture of surface-active substances located at the air-liquid interface and preventing the collapse (sticking together) of the alveoli walls during breathing. - Ed.).

Siberian scientists are also developing drugs with a direct effect on coronavirus — inhibitors of the main protease of SARS-CoV-2. Nikita Aleksandrovich Kuznetsov, Doctor of Chemical Sciences and Head of the Laboratory of Genetic Technologies at the Institute of Chemical Biology and Fundamental Medicine of the Siberian Branch of the Russian Academy of Sciences, commented: “There are many candidate substances that can influence each of these five processes. The two most developed areas at present are inhibitors of viral proteases and inhibitors of viral RNA polymerase.”

The Institute of Chemical Biology and Fundamental Medicine of the Siberian Branch of the Russian Academy of Sciences, together with other research organizations, is also participating in the project to develop inhibitors of the main protease of the virus. Scientists have already created a test system for screening low-molecular compounds based on the fast kinetics method, including the characterization of the mechanism of interaction of the wild-type protease and its mutant form with substrates and inhibitors. Another stage - docking (calculations and modeling) of low-molecular compounds in the active center of the protease - is currently undergoing experimental testing (in vitro screening). Chemical synthesis of new compounds based on the structure of the active center of the protease is also currently underway. Then, specialists will analyze the cytotoxicity and antiviral activity of the compounds in cellular and animal models.

Head of the Laboratory of Physiologically Active Substances, Department of Medical Chemistry, Novosibirsk Institute of Organic Chemistry named after N. N. Vorozhtsov, SB RAS, Corresponding Member of the RAS Nariman Faridovich Salakhutdinov spoke about the prospects and problems associated with the development of low-molecular inhibitors of the SARS-CoV-2 virus. According to N. Salakhutdinov, two drugs: Molnupiravir, registered in November this year in the UK, and Paxlovid, are the most promising and are at the finish line.

"I have no doubt that in six months to a year these drugs will appear on the market, the question is whether this will happen in Russia, and if so, will they be available to a wide range of consumers and to the country's budget? Therefore, the issue of developing a domestic low-molecular antiviral drug is very urgent," Nariman Salakhutdinov emphasized.

Since February-March 2020, the Institute of Organic Chemistry SB RAS, together with the State Research Center of Virology and Biotechnology Vector, has been working on this topic. Scientists have created a pseudo-viral system with the S protein on the surface, discovered leading compounds, and developed a non-pathogenic test system for the main SARS-CoV-2 protease, allowing work in normal, non-specialized conditions. “The most important thing we did was to screen more than 700 original compounds of different classes using the SARS-CoV-2 infectious virus, among which we found 15-17 promising agents with micromolar activity,” Nariman Salakhutdinov emphasized. “They are currently being studied on different strains and animal models.”

Boris Moiseevich Kershengolts, Doctor of Biological Sciences and Chief Researcher at the Institute of Biological Problems of the Cryolithozone of the Siberian Branch of the Russian Academy of Sciences, Republic of Sakha (Yakutia), spoke about the use of the biopreparation "Betucladin" in the prevention and rehabilitation of patients who have had COVID-19.

The preparation is a mechanochemically activated supramolecular complex of bioactive substances isolated from birch bark and thalli of lichens of the genus Cladonia.

When the main mechanisms of COVID-19 pathogenesis were clarified, specialists from the Institute of Biomedical Problems of the Siberian Branch of the Russian Academy of Sciences suggested that Betucladin could have a good comprehensive effect in the prevention and rehabilitation of patients who had had COVID-19, in all the main aspects of the pathogenesis of this disease and without negative side effects. In 2020-2021, scientists conducted clinical trials of the drug's effectiveness in preventing COVID-19 and relieving post-COVID syndrome. According to the researchers, the use of the drug helped to reduce the duration of the rehabilitation period and the severity of its course.

Director of the Eurasian Institute of Zoonotic Infections of the Federal Research Center for Fundamental and Translational Medicine, Doctor of Biological Sciences Alexander Mikhailovich Shestopalov, recalled that wild animals and their migrations play a huge role in the spread of infections. “Of the more than 1,400 pathogens dangerous to humans, approximately 64% are zoonoses,” the scientist commented.

Alexander Shestopalov named the very poor study of animal migration routes, particularly birds, as the main problem that requires an urgent solution. "Since 2002, we have been regularly monitoring bird flu in Siberia and the Far East, and on average about 10% of wild birds carry one or another variant, that is, they are a natural reservoir of mutations of the dangerous virus. However, the last serious work on migration was carried out in the late 1970s at the Institute of Animal Taxonomy and Ecology of the Siberian Branch," the scientist emphasized. In addition, over the past time, air routes have changed significantly, but the reasons for this have not yet been studied. "It is important and necessary to resume research into migration flows, we should begin developing accurate and inexpensive domestic equipment for this, and also pay special attention to the training of ornithologists," Alexander Shestopalov suggested.

NSU Professor, Doctor of Medical Sciences Sergey Danilovich Nikonov spoke about the possibilities of photodynamic therapy. "Only by influencing the features of pathogenesis and the virus itself, we will be able to resist this evil. There are targets that can be affected by light energy and photosensitizing substances," the scientist said. He noted that this project is actively developing and has already received quite encouraging results. One of the pilot installations for this was created in collaboration with the Institute of Laser Physics of the Siberian Branch of the Russian Academy of Sciences.

At the end of the first day of the General Meeting of the SB RAS, scientists discussed mathematical models of the spread of COVID-19, which were created in research institutes using different approaches. Director of the Institute of Computational Mathematics and Mathematical Geophysics of the SB RAS, Doctor of Physical and Mathematical Sciences Mikhail Aleksandrovich Marchenko spoke about a new method born in the Monte Carlo school of methods. "We managed to build a computationally efficient numerical model, and it does not contradict, but complements the one built on the basis of differential equations by our colleagues," said Mikhail Marchenko. - In addition, it is important that we have obtained a way to significantly speed up calculations by combining all six Poisson flows of the model into one. I would also like to emphasize that our model is an imitation of a real process, when levers and measures of influence can be taken into account."

Chief Researcher of the Institute of Mathematics and Mathematical Geophysics of the Siberian Branch of the Russian Academy of Sciences, Corresponding Member of the Russian Academy of Sciences Sergei Igorevich Kabanikhin reported that the model created by their research group is at the level of world standards due to the use of mean field game theory. “The population is divided into groups, relationships and transitions between them are set. However, there is a problem: if we knew the initial data and exact coefficients, we would understand exactly what is happening. However, there are no such coefficients, because COVID-19 is a fairly unstudied disease,” said Sergei Kabanikhin.

Nevertheless, scientists have found a way out: using the information that comes in every day, they can try to solve the inverse problem and restore the missing data, and then calculate a possible scenario based on it. "We have combined the two approaches into a complex model, one complements the other, the data is mutually recalculated. We also actively use a set of artificial intelligence tools," commented Sergey Kabanikhin.

Developing the model, the researchers began to include additional parameters, such as the density of distribution of people in groups, where the variable changes from 0 to 1 and means compliance with quarantine measures. In addition, it is possible to determine the impact of certain measures, to see how different scenarios can be implemented.

The second day of the scientific session of the General Meeting of the Siberian Branch of the Russian Academy of Sciences is devoted to environmental issues and the carbon agenda.