Prof. dr hab. Magdalena Gabig-Cimińska from the Department of Medical Biology and Genetics of the UG Faculty of Biology and the Laboratory of Molecular Biology, Institute of Biochemistry and Biophysics of the Polish Academy of Sciences (IBB PAN) collected data and prepared research paper on studying and using SARS-CoV-2 ‘weak spots’ in COVID-19 treatment.
- Although we learned a lot about COVID-19 diagnostics and treatment during the last few months, we still do not hear enough about basic studies that would enable a better understanding, exactly how SARS-CoV-2 infects people and reprograms human cells to be sick and even kill other cells. In the face of the ongoing public health crisis, research teams of all sizes have been established around the world to take on this problem, trying to not only develop rapid virus diagnostic test (screening test) but also COVID-19 treatment methods, both symptomatic and causative – UG researcher informs us.
To understand the intruder
In March of this year my article was published ‘Lek coraz bliżej. Setki naukowców próbują zrozumieć koronawirusa’ (The medicine is closer. Hundreds of researchers try to understand the coronavirus), where I described the beginning of fight against SARS-CoV-2. Almost six months have passed since then and researchers around the globe have ‘turned their labs upside down’, discovering mysteries of the coronavirus, extending the universal knowledge on this particular pathogen, generating massive amounts of biological data and analyzing those sets searching for clues to fight COVID-19, in order to find a cure for this disease. The ever increasing research team from the Quantitative Biosciences Institute (QBI) from the University of California, San Francisco, USA (https://qbi.ucsf.edu1) is leading the charge in this matter, in coalition with the following research institutions: Icahn School of Medicine at Mount Sinai, in New York City, The Pasteur Institute in Paris, University of Freiburg in Germany and the European Molecular Biology Laboratory in Cambridge, England. Scientists work, literally day and night, to learn how this specific virus attacks human cells, wishing to apply block and lock approach, to understand its spread among human lung cells. For this purpose, they developed the novel ‘molecular fishing’ system to generate instant hints on coronavirus ‘weak spots’ and use them to scour through vast medications databases, searching among all medicines that could stop SARS-CoV-2 available on the market.
Coronavirus map
The core objective of the project and researchers’ work was to create the coronavirus functioning map. Firstly, they created initial ‘protein-protein’ map, which gives the comprehensive view of how coronavirus takes control of human cells, mixing own proteins with human proteins. This map shows all proteins of the pathogen and all proteins found in human body, that could interact with the virus proteins. Viruses cannot survive on their own, they need human host’s cells to multiply. The map revealed 332 various ‘protein-protein’ interactions – the wealth of information on coronavirus protections for its effective propagation inside the human body. Secondly, the map was used to identify the existing medicines and compounds, which kill coronavirus in lab tests and might potentially be used in COVID-19 treatment. The results of researches were published in Nature in April this year. The good news is that thanks to ‘molecular fishing’ the QBI team managed to find around 50 medicines approved by the American Food and Drug Administration (FDA), identifying mechanisms of treatment effects of said medicines on SARS-CoV-2 infection. After analyzing hundreds of experiments, researchers confirmed that some medicines indeed fight the coronavirus, whereas others unfortunately increase host cell susceptibility to infection. What is interesting, the anti-cancer medicines, cancer cells growth inhibitors, were among the identified medicines fighting SARS-CoV-2. Researchers then pondered what coronavirus and cancer have in common. Well, turns out viruses and cancer have much more in common than one would think. Cancer is basically a broken cellular machinery in the human body, which generates uncontrolled growth of human cells. Viruses also interfere with the host’s cellular machinery but instead of generating growth of body cells the machinery in this case is adjusted to grow larger number of viruses. Turns out, coronavirus and cancer, progressing in the same parts of human cells, need to modify a specific type of protein, kinase to grow. Protein kinase operates a cellular switch for majority of biological processes and proteins controlled by them in the human body. That way, identifying anti-cancer medicines, protein kinas (same as taken over by SARS-CoV-2) inhibitors, turned out to be crucial.
Coronavirus in charge
The fact that SARS-CoV-2 uses protein kinases to take over and control human cellular machineries was the reason researchers developed second, more precise, map of virus interactions with various human protein kinases. For years, researchers suspected that protein kinases – biological control switches, used by viruses to take over human body cells – might be target for infection fighting and be the grounds for developing potential COVID-19 medicines. Protein kinases are enzymes present in every cell of the human body, which control structure and information flow. There are 518 human protein kinases, which serve as main control centers of almost every process happening in the human body. They have major influence on human height, stem cells reproduction, immune system, memory and learning. Kinases are particularly prominent in signal transduction, it is a type of control system, like silicon gates on a computer microchip, or traffic light system in the city. They are able to add a small chemical marker to other human cells, slightly altering their structure in a biological process called phosphorylation, thus influencing when and how many of them work. Because proteins are microscale work horses of the cell, they build tissues and trigger chemical reactions, which control all types of organism’s activities, those deceivingly small changes might have large influence on protein functioning, unlocking new possibilities for them. The process of phosphorylation is, in other terms, a change of human cell biological ‘cabling’. For example, if a cell prepares for growth – say to regenerate tissue after injuring a finger – specific protein kinases are activated and start transducing information to proteins responsible for cell growth. While many types of cancer are caused by the hyperactive protein kinases leading to the uncontrolled growth of cells, there are protein kinases inhibitors effective in cancer treatment . That is why this time researchers studied the capacity of coronavirus to manipulate the powerful biological process, phosphorylation. The results of this research was published in Cell magazine in August 2020.
As already mentioned, many anti-cancer medicines target protein kinases. SARS-CoV-2 also uses protein kinases to harm human body – to take over human cells and switching them to the virus command. Researchers determined that learning more about ways the virus ‘speaks’ to cell protein kinases would enable developing medicines, which would suppress the conqueror. For that reason they worked out the list of phosphorylated proteins in healthy cells and the separate list of phosphorylated proteins in infected cells. Next step was to compare both lists and map out differences between the ‘infected and non-infected lists’, thus specifying which protein kinases are used by the coronavirus to grow.
Cocktail in a lab and at clinical trials
When researchers verified which human protein kinases are used by the SARS-CoV-2 to grow and which proteins it alters, data base was analyzed again to search for the existing medicinal inhibitors of the selected protein kinases. For years now, medicines targeting protein kinases traces have been on researchers’ radar, as potentially significant anti-virus medicaments. Indeed, number of medicines were found, which alter the cell traces controlled by human protein kinases taken over by the coronavirus. On the other hand, most importantly, most of those medicines, some in a form of anti-body mixture – a synthetic version of our immune system’s weapon, have already been approved for human application in cancer treatment, or are at the clinical trial stages and may be quickly implemented in COVID-19 treatment. The research revealed that some of those medicines were effective coronavirus inhibitors in cells, significantly reducing Viremia and decreasing the severity of COVID-19 symptoms in patients. Five medicines proved more efficient in killing SARS-CoV-2 in lab conditions than remdesivir and dexamethasone, the only anti-virus drugs so far, which received FDA’s Emergency Use Authorization for severe cases of COVID-19 this May. Later Great Britain, India, Japan, Taiwan, EU and Australia followed suit.
What is more, the use of electron microscopy enabled researchers to take a photograph of the virus infecting host’s cells, visualizing the pathogen in action, manipulating human cell. What researchers saw in the pictures shocked them: the surface of coronavirus infected human cell was covered with slender pipes, or sharp-edged straws, resembling human fingers, called filopodia in biology. They protrude from the infected human cell, piercing wholes in its membrane, creating tunnels going outside. Usually pathogen is dispersed by changing the infected host’s cell into a ‘virus factory’. A cell fills up with virus copies like a balloon fills up with water, it finally burst and frees new virus particles. Numerous, long filopodia spotted in SARS-CoV-2 indicated that the virus developed additional infection method: after growing in human cell – before it bursts – virus gets out of host’s infected cell through filopodia, piercing the neighboring not-yet-infected cell and allowing the virus to move from one cell to another. Similar filopodia were discovered in other viruses, like smallpox, but never that numerous and never that long. Tests and microscope photos revealed that those filopodia – pseudo-arms, were filled with coronavirus copies. What is hard to believe, some filopodia could even branch out like trees, enabling single structure to pierce two human cells concurrently. It has been established that SARS-CoV-2 can use filopodia as virus highways to transport new viruses to neighboring cells, aiding infection spread and effective viremia.
However, it is not the only thing to get excited with. It turned out, the same protein kinases, used by SARS-CoV-2 to infect and multiply in human cells, are used by related SARS-1 and MERS coronaviruses. So, if any developed medicine works and stops SARS-CoV-2, most probably it would also be effective for COVID-22, COVID-24, or any future iterations of COVID that may appear. There are still mysteries that researchers need to solve as they continue their extremely fast-paced research, in order to understand why the virus selects and uses the specific human body signal transducers – protein kinases. They are also not yet sure, whether filopodia stop growing when target kinases are blocked, reducing viremia spread. Researchers are highly optimistic and claim that soon they will be able to select the totally effective medicine (or medicines) for COVID-19, out of the previously mapped out types. QBI Team’s efforts have already resulted in over a dozen clinical trials of potential COVID-19 treatments. Additionally, following the favorable research, some of the medicines may be mixed with remdesivir and dexamethasone to create ‘cocktail’ treatment for COVID. Researchers know beyond doubt that there exists a mixture of medicines – somewhat of a ‘cocktail’, which will cure COVID, but it requires smarts and fast pace to find it.
The achievements described above materialize almost every day. Parallel to clinical trials, COVID-19 patients may, in exceptional cases, be granted access to experimental treatment developed in laboratory, depending on the individual case. This is what happened with one of the most world famous COVID-19 patient, president Donald Trump. It needs to be added, he is not the first patient granted access to yet unauthorized treatment (containing antibodies), being nothing but a synthetic weapon of our immune system against viruses (but also cancer cells), together with remdesivir as ‘cocktail’ treatment for COVID-19.
The article based on:
2 https://www.nature.com/articles/s41586-020-2286-9
3 https://www.cell.com/cell/fulltext/S0092-8674(20)30811-4