A promising approach for antiviral drugs development

Methods for creating antiviral drugs.

Andrey Sokolov, Tatiana Renna.

Abstract. The article describes a schematic diagram of the creation of a new class of antiviral drugs. Examples of experiments that confirm the efficiency and technical feasibility of the proposed scheme are given.

The proposed scheme makes it possible to turn the "minuses" of viruses (high mutation rate and intracellular reproduction) into "pluses" for the creation of effective antiviral drugs.

A fundamentally new approach to the creation of antiviral drugs using fake cells and other methods of deceiving the biology of the virus makes it possible to create a wide range of effective antiviral drugs.

Algorithms are proposed for creating antiviral drugs for the treatment of respiratory, intestinal, transmissible viral infections, as well as for creating a drug for the treatment of COVID-19 disease caused by the SARS-CoV-2 coronavirus.

Keywords: virus, medicine, COVID-19, SARS-CoV-2, antiviral drug, respiratory virus, fake cell, receptor, infectious diseases, viral infections.

The urgency of the problem.

Despite a fairly wide range of antibacterial drugs, the choice of antiviral drugs for the treatment of infectious diseases is very small. For many years, attempts to create antiviral drugs by analogy with antibacterial (blocking the multiplication of the virus, killing viruses) have not led to significant success.

Our proposed approach to the creation of antiviral drugs is based on a fundamentally new view of the inactivation of viruses inside the human body.

At the present stage of biotechnology development, the algorithms we propose can be implemented rather quickly and relatively cheaply.

If we use analogies, then we propose not to invent or use guns and bullets to destroy viruses, as is the case with the use of antibiotics, but to use, like on a fishing trip, a kill-devil - a fake fish, which the virus itself will seek and catch and, as a result, inactivated , self-destruct.

Create a fake cell to inactivate respiratory viruses.

Compared to the wide range of antibacterial drugs, the spectrum of antiviral drugs is very small. This happens for two reasons. The first is the high rate of mutation of viruses, which allows them to elude developed drugs. The second is intracellular reproduction and the peculiarities of the functioning of viruses inside the cell, which complicate the effect of drugs on them.

These features can be called the strengths of a viral infection. And at the same time, this is their weak point.

To penetrate into the cell, the virus must interact with the surface structures of the cell. These structures are stable, which means that the components of the virus interacting with them must also be stable. And this is the "Achilles' heel" of viruses, despite the speed of their mutations. This is the first constant that could help create a new class of antiviral drugs.

The elusiveness of the virus inside the cell is the second traditional obstacle to the creation of antiviral drugs. But at the current level of development of biotechnology, it also turns into the "Achilles heel" of viruses. For reproduction, the virus needs cell structures - organelles, genome, special molecules. No cell - no virus multiplication.

Based on these features of the life cycle of viruses, a schematic diagram of the creation of a new class of antiviral drugs was proposed. [1,2]

The essence of this principle is the creation of a phospholipid bubble - a fake cell, with receptors attached to the surface, to which the virus attaches and begins the process of penetration into the cell.

Once in a fake cell, the virus begins to prepare for reproduction, loses its shell, etc. If the fake cell is filled with cleaving enzymes, then the structures of the virus are immediately subjected to cleavage. If the sphere is filled with an inert substance, then the fake cell becomes a "mousetrap" for viruses that cannot multiply, because there are no cell structures and molecules necessary for this.

An example of how this can be done is the placement of receptors (angiotensin converting enzyme 2 (ACE2) and CD147) on the surface of nano-sponges, which are essentially fake cells, resulting in the absorption SARS-CoV-2 virus to nano-sponges. As a result, the reproduction of the virus stops, and the viral particles are destroyed. [3] The effectiveness of this concept has been tested in vitro. [4]

Thus, nano-sponges covered with a phospholipid membrane with receptors complementary to the virus are an active prototype of a “fake cell” capable of catching any virus, depending on the membrane structure and receptor characteristics.

Thus, a fundamentally new application for nano-sponges was found and the efficiency of the proposed [1,2] scheme for creating antiviral drugs was tested.

This allows the development and creation of a new type of antiviral drugs in many pharmaceutical companies around the world.

Possible areas of application of the scheme "fake cell + receptor" and options for improving this scheme.

In addition to the receptors for SARS-CoV-2, on the surface of nano-sponges, according to the proposed scheme [1,2], it is possible to place molecular structures used by other respiratory viruses (adenovirus, influenza, etc.) to penetrate the cells of the body. In addition to respiratory viruses, the proposed scheme receptor + fake cell can be used to create antiviral drugs against viruses that use blood cells (HIV, etc.) and gastrointestinal epithelium (rotavirus, etc.) for multiplication.

In addition, the scheme for creating a new class of antiviral drugs can be improved by modernizing the fake cell itself.

You don't need to use nano-sponges, or otherwise create a phospholipid bubble or fake cell. A portion of the cell membrane and receptor is enough to trigger the "deception" and deactivation of the virus.

Having established contact with the receptor, the virus starts a cascade of reactions leading to its "unpacking" and, under the conditions of the cell, ending with the creation of new viral particles. But this requires a real cage. Reproduction of the virus will not occur in a "fake cell" without organelles and the genome of the macroorganism, will not occur in the intercellular space, the lumens of the bloodstream, gastrointestinal tract, alveoli and bronchi.

This means that you can create a drug that mimics only a part of the membrane + the receptor. This will lead to the unpacking of the viral particle and the release of genetic material into the void (into the bloodstream, intercellular space, into the lumen of the gastrointestinal tract, alveoli or bronchi), where the virus cannot multiply, and its molecules will be destroyed by molecules and cells of the human body.

But you can also get rid of such components of the drug as "fake cell" or "fake membrane".

To penetrate a cell, the virus does not use the entire structure of the receptor, not the entire complex of molecules that cover the cell, but only a small part of them. This means that on the basis of the proposed principle [1,2], it will be possible to create a medicine containing only a significant part of the receptor on a substrate inert for the body. This will reduce the cost of creating and producing the drug, the final price for the consumer, as well as reducing the risk of unwanted side effects, such as allergic reactions.

The most elegant scheme, observing the "bait" principle, but modernizing the solutions proposed above, is the use of recombinant human angiotensin converting enzyme 2 (rhACE2) as a treatment for patients with COVID-19 (APN01-COVID-19) [5,6 ]. A similar scheme can be used for other viral diseases by synthesizing a receptor corresponding to a specific virus.

Creation of new anti-viral medicines.

Synthesis of highly avid artificially developed receptors can become a promising way to create a new class of antiviral drugs. [7]

In order to cause an infectious disease, a virus needs to enter a human cell. He does this by forming a bond between the proteins of his (viral) capsid (membrane) and receptors on the cell surface.

The virus obtains this opportunity through mutations. The most striking example of such evolution is the COVID-19 epidemic, when the SARS-CoV-2 coronavirus, which bats have used for its reproduction for many millennia, acquired a mutation that allowed it to bind to ACE2 receptors on the surface of human cells.

In order to create an effective antiviral drug, you need to understand that the combination of proteins of viruses with a receptor has a number of features and even disadvantages.

The fact is that the perception of the classical "key-lock" scheme for combining antigen and antibody, neurotransmitter and receptor, viral proteins and cell receptors has a significant simplification. Counterparties (neurotransmitters, antigens) attach to the same receptor, to the same antibody with different strengths. Those, if we follow the analogy of a key-lock, then in addition to a real, ideally suitable key, several more worse keys can be suitable for the same lock, in fact - picklock.

Viral proteins, unlike human proteins, are more like picklock than keys. Their connection is less strong. The virus does not need to start any processes in the human body - it only needs to enter the cell.

However, human proteins don't bind perfectly to the receptor either. They bind enough to compete with other proteins for this receptor.

This suggests that it is possible to artificially develop and synthesize a receptor that will bind the virus capsid proteins much more strongly than the receptors of a human cell.

A drug containing such an artificial receptor will compete with the cell receptors for the viral capsid proteins. The artificial receptor will bind to the virus more tightly than the cell's receptor and take on a significant portion of the viral load, preventing the virus from infecting cells.

It is quite difficult to develop such an artificial receptor empirically. And here big data and artificial intelligence can come to the aid of scientists, which will allow them to model the most suitable receptor for the proteins of the viral capsid.

As a result of this simulation, it is possible to obtain a formula of the required substance, which will interact more actively with the virus than the cell of the body. This, in turn, will lead either to blocking the virus, or to its activation "into the void" - self-destruction of the capsid, if the artificial receptor can trigger the beginning of the release of the virus genome into the extracellular space, which in turn will lead to inactivation of the virus and the impossibility of further reproduction.

Basically, the simulation will create a false receptor that tricks the virus, preventing it from infecting the body's cells and dramatically reducing viral load.

The resulting formula will become a starting point for the chemical synthesis of an artificial receptor, after which it will be possible to test the effect of the antiviral action of artificial receptors in laboratory and clinical trials. If the effect is confirmed, it will be possible to create a wide range of new generation anti-viral medicines.

Conclusions.

Different viruses use different mechanisms to enter the cell. But the "weak points" are the same for all - the need to selectively attach to the cell and the need for the presence of cell structures and molecules for the reproduction process.

We believe that all the above options for technical solutions have the right to life and will find their application for specific respiratory, intestinal and, possibly, vector-borne viral infectious diseases in humans.

References

1. Sokolov A.L. Virus Trap // https://gabr.org/teorii/antivirus.htm Posted on 27 Jan. 2020
2. Sokolov A. Creating a new class of antiviral drugs // https://gabr.org/teorii/antiviral_drugs.htm 10 Feb 2020.
3. Qiangzhe Zhang, Jiarong Zhou, Hua Gong, Ronnie H. Fang, Weiwei Gao, Liangfang Zhang, Anna N. Honko, Sierra N. Downs, Jhonatan Henao Vasquez, Anthony Griffiths. Nano-sponges for deception SARS-CoV-2. The virus recognizes the nano-sponges as a cell and combines with them. As a result, it does not reach a real cell and loses its ability to reproduce. // UC San Diego News Center https://ucsdnews.ucsd.edu/pressrelease/nanosponges-2020 Posted on 17 June, 2020.
4. Qiangzhe Zhang, Anna Honko, Jiarong Zhou, Hua Gong, Sierra N. Downs, Jhonatan Henao Vasquez, Ronnie H. Fang, Weiwei Gao, Anthony Griffiths, Liangfang Zhangcorresponding. Cellular Nanosponges Inhibit SARS-CoV-2 Infectivity // The Journal Nano Letters. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301960/ Published online 2020 Jun 17.
5. Ashley Yeager. Blood Pressure Meds Point the Way to Possible COVID-19 Treatment // THE SCIENTIST. Apr 2, 2020 https://www.the-scientist.com/news-opinion/blood-pressure-meds-point-the-way-to-possible-covid-19-treatment-67371
6. Recombinant Human Angiotensin-converting Enzyme 2 (rhACE2) as a Treatment for Patients With COVID-19 (APN01-COVID-19). // Apeiron Biologics. April 6, 2020 https://clinicaltrials.gov/ct2/show/NCT04335136
7. Sokolov A. Big data and virology. Creation of new anti-viral medicines. // 31 Dec 2020. https://gabr.org/teorii/antiviral_drugs.htm

Contacts: Andrey Sokolov 2336694@gmail.com