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Covid, the search for a cure by studying the genome of the virus

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January 10, 2020. A date destined to enter the history books. It is on that day that the sequence of Sars-CoV 2, the new coronavirus cause of the Covid-19 pandemic, is deposited in databases around the world. A few letters – the genome of the virus is composed of about 30 thousand bases useful for the production of only 7 viral proteins – the knowledge of which is of fundamental importance for understanding its life cycle. Only by knowing the enemy in front of him is it possible to counter him. Thanks to the previous genetic knowledge on Sars-CoV 2 “sister” viruses – and to the new discoveries on the molecular mechanisms by which it penetrates, replicates and exits the cell – today the virus can be successfully countered thanks to the advent of new molecules capable to stop its growth.

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One of the most delicate phases of the infection is the entry of the virus into the host cell. This is where the main game is played. This occurs thanks to the spike, a protein placed on the surface of the virus, which serves as an anchoring site for the Ace-2 receptors placed on the host cell. Thanks to in-depth studies on the mechanism by which the virus “hooks” to Ace-2 it has been discovered that the spike is camouflaged to evade the immune system thanks to the presence of “sugar” molecules, glycans. An expedient implemented in order not to be recognized and to carry out its life cycle undisturbed. Not only that, the presence of these sugars helps the spike protein to improve the bond with the cells to be infected. But it is precisely this characteristic that in the future, for many viruses that share the same mechanism, could be exploited to our advantage. A study by the University of California San Diego has shown that by changing the composition of glycans it is possible to reduce the infectivity of the virus by decreasing its ability to bind to the host. A potentially useful mechanism in the search for new drugs capable of “defusing” the strength of Sars-CoV 2.

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But to think that virus entry depends on a simple interaction between spike protein and Ace-2 is an understatement. Also in this case, structural genomics comes to our aid: according to a study carried out by Martin Beck of the Max Planck Institute, the spike is not at all a “key” that fits into the lock, but something extremely versatile and mobile capable of considerable flexibility in going to look for the receptors to which it can be anchored. Not only that, to this particular feature is added that of the ability to change in some particular portions responsible for the link with Ace-2. As explained on the pages of the magazine Nature gives Priyamvada Acharya, a structural biologist at the Duke Human Vaccine Institute in Durham: “The modifications that occur in the S1 portion of the spike protein help the virus to enter cells more easily.” And this is the case with the variants. The Delta, the one prevalent worldwide, thanks to these modifications has become extremely more contagious than the original version of the virus isolated in Wuhan.

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In spite of its size, Sars-CoV 2 represents a concentrate of efficiency that is difficult to match by other viruses. Second Noam Stern-Ginossar, virologist at the Weizmann Institute of Science in Rehovot, there are three mechanisms that Sars-CoV 2 puts in place to achieve the goal. Nothing new that represents, however, a perfect storm. Sars-CoV 2, in fact, would have taken the best parts of all coronaviruses.

The first winning step involves the elimination of “competition”: Nsp-1, one of the first proteins to be produced, has the task of cutting all the mRNAs of the cell that do not contain viral “tags”, that is, all the mRNAs useful for guest to survive. The host cell is therefore at the complete disposal of the virus since this “cut” leads to a reduction in the translation of cellular proteins of over 70%.

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The second is the “turning off” of those alarm signals that the cell puts in place to indicate that it is in difficulty. In fact, in the variants that have emerged to date, some mutations found have caused a reduced production capacity of interferon, a key molecule for activating the immune system in recognizing cells infected by the virus. And it is precisely on these two mechanisms that studies are focusing in an attempt to identify molecules capable of interfering with the Nsp-1 protein.

Inhibit replication

One of the main objectives of all molecules directed against viruses is to inhibit their replication. To do this, it is necessary to study in detail the genome and the structure of the proteins that contribute to this complex process. Thanks to the study on the Sars virus, today we are starting to reap the fruits of research from a Sars-CoV 2 perspective. The goal is to target a component of the virus, the C3-like viral protease, to block its replication. Today all this is possible thanks to paxlovid, a treatment proposed by Pfizer with some small changes in the structure after an initial experimentation 19 years ago against the Sars virus. In this case, the drug, taken orally, belongs to the category of protease inhibitors, a class of molecules already in use in the treatment of HIV and hepatitis C. Paxlovid, which has entered the cells, is able to inhibit the activity of a component, the one that the virus uses to assemble the proteins it is made of. As this ability fails, the virus is no longer able to fulfill its function. To work at its best, however, the treatment also involves the administration of an old HIV drug (ritonavir) which has the task of increasing the duration of action of paxlovid. According to early studies, using this combination within 3 days of symptom onset can reduce the risk of hospitalization and death by 89%. A percentage that is reduced to 85% when taken between 3 and 5 days.

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The Molnupiravir Strategy: Misleading

Different is the strategy for molnupiravir, another drug useful against Sars-CoV 2, developed by MSD and Ridgeback Biotherapeutics. Initially studied as an antiviral against the influenza virus, but since the pandemic “broke out” the molecule has been tested in Sars-CoV 2 positive individuals. The drug in question belongs to the category of nucleoside analogues, molecules similar in structure to “building blocks” of viral RNA. Molnupiravir, once it enters the infected cell, is used as a “building block” for the construction of new viral particles. But the incorporation of this molecule leads the virus to accumulate errors that go to nullify its replication.

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Translated: the virus, full of “copying” errors in its genetic code, cannot replicate itself and survive.

According to the results obtained in the different trials, molnupiravir was able to reduce hospitalizations (and the risk of death) by 50% in patients at high risk of developing severe disease. The effect occurs when the drug is taken within 5 days of the onset of symptoms.

Block the exit

But the search for additional drugs against Sars-CoV 2 is far from over. As the history of viruses teaches – unfortunately the infectious agent, over time, develops long-term resistance mechanisms – it is essential to be able to count on multiple weapons capable of selectively targeting the different mechanisms that the virus puts in place to replicate and infect new ones. individuals. A mechanism that could be exploited in the future is that of the release of new Sars-CoV 2 particles from cells. For years, thanks to the data available on other coronaviruses, it was always thought that viral particles were expelled from the cell through the Golgi complex, an apparatus that through the formation of vesicles transports new viruses from the cell to the outside. With Sars-CoV 2 everything changes: according to a study published by Nature, work of researchers at the National Heart, Lung, and Blood Institute in Bethesda, Sars-CoV 2 instead of exploiting the Golgi complex uses lysosomes as output, structures known for decades to be the carriers of “cellular garbage”. A feature that, according to Carolyn Machamer of Johns Hopkins University, “could be exploited in an attempt to develop new antiviral drugs directed against Sars-CoV 2”.

From the study of the viral genome there are also useful indications for the design of new vaccines. Those currently on the market mainly stimulate the production of antibodies by the B cells of the immune system. But there is another component in the response to the virus, T cells, that could provide the long-term solution. Recently a study published by Nature investigated why some individuals heavily exposed to the virus without vaccination do not develop any response to the virus, such as serological and molecular swab positivity, anyway.

The analyzes showed that in these individuals there were groups of T cells that were particularly reactive against a broad spectrum of viral targets. In particular, the study found that these memory T cells were able to recognize that complex mechanism of transcription and translation of viral RNA. Specifically, the component most affected by the memory T cells of resistant people was viral polymerase, a highly conserved enzyme in all coronaviruses, including Sars-CoV 2. In these individuals, the encounter with other coronaviruses previously allowed for the development of memory T cells capable of recognizing the identical areas of the viral genome between the different coronaviruses. Result? Greater ability to recognize Sars-CoV 2 infected cells in the very early stages of infection.

Having identified this population of cells is now paving the way for the development of new vaccines capable of generating a specific T-cell response. An example is represented by the British biotech Emergex: testing of the vaccine will begin in Switzerland on 3 January on 26 volunteers. To be administered, by means of a patch with micro-needles, will be synthetic molecules that mimic some viral proteins capable of specifically stimulating only T cells. The goal is not to add a new vaccine against Covid-19. to those already present but to provide a useful tool to further improve long-term immunity.

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