New antibiotics for the treatment of tuberculosis are being developed, but…
Russian Biotech lacks strong pharma
Marina Muravyeva, STRF.ru
Priority of Russian scientistsTuberculosis is the most difficult to treat socially significant disease, which for various reasons is not affected by any drug.
To antibiotics, which proved themselves perfectly in the 1960s and 80s, drug resistance has long been developed. The course of treatment can last from six months to several years, but in the end the patient does not recover. Several million people die from tuberculosis in the world every year. First of all, this problem is typical for developing countries, but it exists both in Europe and in the USA.
"We are developing new antibiotics for the treatment of tuberculosis, the causative agents of which are mycobacteria," says Valery Danilenko, head of the Department of Postgenomic Biotechnology at the N. I. Vavilov Institute of General Genetics of the Russian Academy of Sciences. – These are targeted drugs, "targeted" drugs (from the English target – target)."
The search for medicines is now carried out according to a completely different scheme than it was, for example, 10 years ago. Then drugs were created, their effectiveness was tested, and if it was possible to cure a particular disease, then they were used. Sometimes the mechanism of action of the drug was found out only after decades, as, for example, it happened with aspirin (the main biomishen became known several years ago). As a consequence of this approach, there are serious side effects from the use of drugs for humans.
About 10 years ago, the direction of creating biomishen-directed drugs, including antibiotics, began to develop in the world. First, using the methods of genomic, computer analysis, they look for specific target proteins that would distinguish the bacterium, that is, so that the bacterium has them, but the person does not have them. In extreme cases, they should be both there and there, but in humans they would be resistant to these drugs, and in bacteria they are sensitive. Then the genes encoding these proteins are isolated, cloned, obtained in the form of specific molecules, their crystal structures are created on the basis of these proteins and their interaction with the drugs being created is evaluated. Then, based on them, test systems are designed in vivo, in vitro for testing methods of mass screening and subsequent improvement of substances in order to create a drug.
This approach is also used in the department of Valery Danilenko when creating new drugs for the treatment of tuberculosis. The research is carried out within the framework of the RAS program "Fundamental Sciences – Medicine" and the Federal Target Program of Rosnauki "Research and Development" (project topic: creation of a new type of antibiotics for the treatment of socially significant infectious diseases complicated by multidrug resistance).
The authors came up with the idea that protein kinases (a subclass of kinase enzymes that modify other proteins by adding phosphorus, which leads to a change in their activity) can be used as biomishens, and that a combination of inhibitors of this mycobacterial protein kinase and one of the human protein kinases can be the most effective means for removing the virulence of the pathogen. With such a combined effect, on the one hand, on human protein kinases, and, on the other hand, on mycobacterium protein kinases, ensuring their virulence and viability in infection, it is planned to create fundamentally new drugs. It is assumed that resistance to these drugs will not occur.
"The creation of antibiotics that cause selective programmed death of mycobacteria in chronic patients is a new look at the creation of drugs," notes Valery Danilenko. – The idea is fundamentally new, the biomishen is fundamentally new, and the approaches are fundamentally new. No one else is using them yet. It is possible to remove virulence – this is one approach, not only we work with virulence, but also other scientists in Europe and the USA. As for the programmed modulation of bacterial death, no one else is working in this direction. The phenomenon of apoptosis, programmed death of cancer cells, is well known. In bacteria, this is only at the stage of primary research, and here we have priority."
With hope for Europe?After the new biomishens are developed, the stage of obtaining the drug and conducting preclinical studies will follow.
For this group of substances, this can be implemented in about three years. Together with colleagues-chemists from the Institute of New Antibiotics of the Russian Academy of Medical Sciences (Prof. M. N. Preobrazhenskaya), a number of substances that can be used in the treatment of tuberculosis were obtained. Subsequent clinical trials are a very expensive process, Professor Danilenko notes, which requires tens or even hundreds of millions of dollars. In terms of time, it can take from 5 to 7 years. And it will require the mandatory participation of a large pharmaceutical company that will be interested in promoting these drugs to the market, and not only to the domestic, but also to the world.
The problem is that even large pharmaceutical companies practically do not deal with antibiotics, more precisely, cheap antibiotics that are used to treat social diseases. Expensive antibiotics for personal treatment, they create, in particular, anti-cancer biomishen-targeted drugs. "In Russia, they do not deal with any antibiotics and do not plan, because it is difficult, requires large investments," says Valery Danilenko. – There were six factories in our country that produced antibiotics. In 1990, Russia ranked second after the United States in terms of antibiotic production. Now production is stopped. Substances of other medicines are also almost not manufactured. Existing pharmaceutical companies in Russia cannot do this, and there is no money, and there is no desire."
Major global companies do not want to engage in development at risky stages of the creation and promotion of medicines, including antibiotics. Venture capital is engaged in the promotion of primary hit connections. In Russia, it is weak, so some of the functions are assumed by RAS, Rosnauka. When the drug passes preclinical tests and shows good results, then large companies are happy to buy them. All over the world (in the USA, in the EU, and in Russia), the treatment of diseases such as tuberculosis, HIV, and influenza is given great attention by states. Without government support and funding, it is unlikely to be possible to solve these problems. Even large pharmaceutical companies.
Valery Danilenko's research team in this situation is encouraged by the fact that their laboratory is a member of the European consortium (within the framework of the FP6 program) to create target-directed drugs of the post-genomic era of a new generation. These are primarily anti-cancer drugs. Currently, the issue of creating a European consortium for the development of biomishenes and drugs for tuberculosis within the FP7 program is being resolved in October of this year. The EU has identified this topic as the most important state problem. One of the largest EU scientific consortia on this issue should appear. The laboratory of Valery Danilenko received an offer to participate. Scientists hope that they will be able to take part in this promising project.
It will be formed as follows. At the first stage, an initiative core of major scientists with a worldwide reputation and weight for EU governments are working out the importance and prospects of implementing a particular direction, it is determined that this medicine and this problem is key for the EU, for medicine. Then they select laboratories in Europe, including Russia, which could become members of the consortium. A team is being formed, which may consist of 25-30 laboratories from different countries. A project is being created and submitted to the EU for an appropriate competition. There is a competition for large projects worth tens of millions of euros. Next comes the implementation. These projects are supervised by experts, consultants from the government and relevant EU structures. From the very beginning, representatives of medium-sized businesses participate in the research. One of the tasks of the consortium is to promote the development of the pharmaceutical market, as well as the search for business partners.
Need a bigpharmaSpeaking about the prospects for the development of the pharmaceutical industry in Russia, Valery Danilenko notes that the key problem is related to the fact that there are no large pharmaceutical companies in the country capable of implementing large-scale tasks to create new drugs.
Perhaps, within the framework of the PHARMA 2020 strategy, with a proper understanding of the situation on the part of the state and the public, as well as the availability of a scientific and technological base, a large Russian pharmaceutical company will be created. In addition to its purposeful creation, another option is also possible, Danilenko believes. For example, if one of our big businessmen decides to diversify and make significant investments in the pharmaceutical industry. In a crisis, this is quite appropriate. Despite the fact that in the world, and in Russia, there is a decline in all spheres, the pharmaceutical industry has practically not suffered. The number of employees has not decreased, the market has not decreased. This indicates the stability and prospects for the development of this direction.
"Of course, we are interested in the fact that clinical trials of medicines created by us are also conducted in Russia. There are all possibilities for this. Besides, it would be cheaper, – says Valery Danilenko. – However, if we proceed from the current situation, it will be necessary to hold negotiations with major pharmaceutical companies in the world on further promotion of medicines. An important point here is an agreement with a Western company to ensure that production and sales in the Russian market are carried out on favorable terms for the population of the country. The drug is socially significant. Many hundreds of thousands of people get sick and die from tuberculosis in Russia and the CIS countries."
In addition to the absence of big pharma, another problem of the underdevelopment of the Russian pharmaceutical market is connected, according to Danilenko, with the policy pursued in this direction. "Until recently, there was a policy that Russia does not need its own drug development, the West will do everything," says Valery Danilenko. – There were no adequate experts who could correctly select drugs, form a strategy. It appears in the Ministry of Industry and Trade, and I hope it will also appear in Rosnauke."
To date, the state has done a lot to create an infrastructure in Russia for the development of the pharmaceutical industry. The concept was developed, a specialized department was created in the Ministry of Industry and Trade. Under the auspices of the Academy of Sciences, work was carried out on the inventory of projects, consolidation of scientific forces.
After a year and a half of intensive work, in which the Russian Academy of Sciences and many specialists of the Russian Academy of Sciences actively participated, the "Strategy for the development of the pharmaceutical industry of the Russian Federation for the period up to 2020" was prepared. The strategy states the need to develop 200 innovative drugs. According to Valery Danilenko, this task is real. The developers of the document have repeatedly noted that 200 innovative drugs do not all have to be original. These may be new forms of delivery, new dosage forms, as well as patentable generic analogues. Only a few blockbusters with billion-dollar sales can be created before the year 20. Perhaps there will be 3-5 of them. But this does not contradict the figure 200. It should be borne in mind that no business is complete without advertising, and scientists around the world, in order to convince and attract the attention of the government, often say what is expected of them, not deceiving, but somewhat embellishing the situation.
"We have strong chemists, not all of them are engaged in medical chemistry, but some are starting to turn in this direction," says Valery Danilenko. – Many bioinformatics specialists who are engaged in computer-aided drug design in the USA, England, Germany are Russian scientists. We have good natural bioresources for screening biomolecules: there are laboratories in the Far East, in Novosibirsk. Not only chemical synthesis, but also isolation from natural sources: microorganisms, plants, algae, will make it possible to obtain new original medicines, including antibiotics. Our department specializes, it seems to me, successfully, in the search for new biomishens, the creation of new test systems for screening, the creation of new technologies for the search and selection of targeted drugs. So with a competent formulation of the task, everything can be done, the main thing is that someone needs it."
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