Covid-19: here is how SARS-CoV-2 breaks into cells. What can research do about it? More than a vaccine.
Prevention is the best way to fight viral infections, and it’s achieved by vaccinating the population. When we talk about vaccines, it is crucial that coverage of vaccinated people is the highest possible, to prevent the spreading of the infection. Prevention is so important because for most viral infections there is no cure. Most of them are neither lethal nor severe, and diseases are self-limiting. This means that the organism is able to defeat the virus by itself. The only help comes from pain and drug relievers, like ibuprofen or paracetamol, which anyway do not directly fight the virus.
Why is it so important to prevent spreading of viruses? Because there are some categories at risk, such as older people, or immunosuppressed, or people with other pathologies that could make the viral infection more severe and potentially lethal.
So why there are no treatments beyond prevention? Treatments are available for certain pathologies, such as hepatitis C, but not for all. This because it’s difficult to produce drugs that target viruses. Viruses are different from bacteria and other pathogens from both structural and mode-of-action points of view. Viruses don’t have a nucleus, or a cell wall that could serve as target. Moreover, they survive by replicating within the host cell, exploiting cell’s tools, and in this way they hide from immune system surveillance. A cell infected by a virus is like a hijacked airplane. The cell has few ways to send out an SOS when infected:
- like a passenger on the plane can secretly take a photo to the hijacker and send it to the police, the cell can expose on its surface pieces of the replicating virus, and the S.W.A.T. of the immune system receives the message and get into action;
- alternatively, the cell itself can begin a silent “onboard” rebellion by releasing interferon, which both hampers replication of the virus and asks for external help;
- last but not least, antibodies serve as guardians to target virus particles that exit the cell to spread the infection.
In the first two cases, the final result is the destruction of the infected cell, being not possible to kill the virus in another way.
Deep investigation has to be done into the mechanism of action of viruses. Potential targets are the way the virus enters the cell, the replication process and the assembly of novel viral particles in the host cell. If we know which molecule on the cell surface is exploited by the virus to enter the cell, it’s possible to prevent that interaction, therefore limiting the infection. In similar way it’s possible to hamper the virus replication and proliferation. Each virus acts differently, so findings are usually virus-specific. For example, thanks to this knowledge, it was possible to develop therapies against HIV, which significantly extended lifespan of infected people.
What’s the research status about the SARS-CoV-2 (causing Covid-19 disease), the infamous coronavirus that is currently spreading in the world?
Recently, a paper published on Cell by Hoffmann and colleagues revealed the mechanism through which the virus enters the cell. Similarly to what happened with SARS and MERS, the spike protein on the virus surface binds to a cell membrane receptor called ACE2. The next step, required to allow the virus into the cell, is the priming of the spike, which is done by a cell protein called TMPRSS2. The good news is that an already existing drug that blocks TMPRSS2 action has been shown to prevent the virus from entering cells. This finding is relevant for a potential clinical study.
Investigating the mechanism of action of SARS-CoV-2 allows to understand which other viruses act similarly, for example in the way of replicating (which is not related to the disease caused). In this way, drugs already tested for the similar, better-known viruses could be tested also for SARS-CoV-2.
Another strategy to develop a drug against SARS-CoV-2 involves the computational prediction of its proteins structure. The genome of each organism contains the instructions to build its proteins, and we have enough knowledge to predict with relatively good results the structure of a protein, given the genome that contains the related instruction. Therefore, the isolation of SARS-CoV-2 genome allows to predict the structure of the viral proteins. It’s not possible to observe the real structure yet, because the employed techniques requires several months of optimization, being extremely sensitive. In the meanwhile, artificial intelligence is exploited to hypothesize the most conceivable shape. Jumper and colleagues revealed on Nature that they managed to predict the structure of the spike protein, which is required by the virus to enter the cell. This and Hoffmann’s results provide a good start in the search of an efficient targeted therapy.
John Jumper, Kathryn Tunyasuvunakool, Pushmeet Kohli, Demis Hassabis, and the AlphaFold Team, “Computational predictions of protein structures associated with COVID-19”, DeepMind website, 5 March 2020, https://deepmind.com/research/open-source/computational-predictions-of-protein-structures-associated-with-COVID-19