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COVID-19 and cellular biology: new screening tests and antiviral strategies

Elsa Champion
04/27/2020
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Four questions for Franck Perez, CNRS Director of Institut Curie’s Cell Biology and Cancer unit
Franck Perez

Franck Perez

You’re launching a number of projects for COVID-19. One of them involves developing new antibody-based screening tests. Could you tell us more about it?

The tests currently available to identify COVID-19 people are based on testing RNA and DNA (PCR tests). However, these tests are expensive and slow, and we are facing a shortage. My team is now working with Institut Pasteur on a project that aims to develop new and rapid tests based on antibodies rather than DNA, which will provide an alternative solution. To do so, we are using an in vitro antibody selection strategy that we have been using in our laboratory for a number of years now, based on the phage display technology that won the 2018 Nobel Prize in Chemistry. The goal of phage display is to identify the interactions between some proteins or peptides and various targets, such as other proteins or nucleic acids, by using a specific type of bacterial virus (phages) to select molecules of interest. In the case of antibody identification the primary advantage of this method is how quick it is, as it gets around a long natural immunization stage in animals. We are drawing on Institut Curie’s “Antibody” platform, which uses libraries of fully synthetic antibodies that we have built. Using this tool, we started to identify antibodies that we may be able to use to detect coronaviruses in patient samples. We are also working with Institut Pasteur to develop quick serology tests that allow us to detect the presence antibodies directed against the virus in people. After the crisis, these tests should allow us to identify people who test positive, individuals who have already caught the virus and who may be protected, as well as those who are high-risk as a result of not being immunized.

What form does the coronavirus used in your upcoming experiments take?

Let me be very clear. At Institut Curie, we do not work with virus strains. We use very good experimental in vitro models, known as ‘pseudo-type’ viruses: these are particles that express some proteins from SARS-Cov-2 (the strain that causes COVID-19), which allow us to replicate the coronavirus’s infection processes, but which are unable to replicate and express no toxic gene. Working with the SARS-Cov-2 strains requires high security levels (P3 laboratories). Although Institut Curie is equipped with these laboratories, my team is not expert in virology, and we will work with specialized teams if and when the need to conduct tests on viruses arises.

Other projects aim to identify active molecules capable of blocking COVID-19 cellular infections. What do these involve?

By their very essence, viral infections are cellular diseases, and cell biology can provide essential insight in this context. All viruses exploit proteins and lipids that are naturally expressed by cells, hijacking them to serve their own interests. Many viruses also use other cellular proteins to become active, thereby entering cells and infecting them. With respect to SARS-Cov-2, its receptor on the surface of cells is ACE2 (Angiotensin-Converting Enzyme 2), particularly involved in regulating blood pressure. Other proteins, like cellular proteases, are also essential for infection.

One anti-COVID-19 solution could potentially be to target ACE2 by preventing it from reaching the surface. This option looks promising, but this protein plays a crucial role and disrupting it appears to impact on how lungs are affected. The other option would therefore be to target and inhibit proteases. Our approach is based on our knowledge about intracellular transport routes. Drawing on Institut Curie’s BioPhenics screening platform, our project aims to identify one or several molecules among the 1,500 included in a bio-bank that encompasses molecules already used as medication (and consequently authorized for use on humans), which could reduce these proteases’ expressions on the surface of cells. We carried out similar screen sin the past and we are thus confident that this project may allow to propose novel treatments for COVID-19. We’ve planned our project over a six-month period: Four months to identify one or several molecules to be used, and two months to evaluate effective doses and study the potential synergistic effects of combined treatments.

Another project is under-way with my colleague Raphaël Rodriguez who leads Institut Curie’s Cancer Biology and Chemistry team, in partnership with a French company. This is a much longer-term project on a wider scale, as we plan on much more extensive screening. Our goal will be to assess a million different molecules to identify a thousand that could have in vitro activity, before validating some of them via cellular tests, and then optimizing them in order to offer molecules that could be used to tackle SARS-CoV-2 or other similar viruses that might emerge in the future.

Any final thoughts?

Our research, and the expertise we gather today to develop novel approaches to respond to the COVID-19 crisis, have been built over the years to understand the fundamental mechanisms of cellular functions, and our investment in high-level technological platforms has allowed us to be incredibly responsive and to quickly put forward projects that aim to develop concrete diagnostic and therapeutic strategies for COVID-19. We feel that it should be a long-term commitment, because COVID-19 may be here to stay for a while in various countries, but also because after MERS, SARS and now COVID-19, it is crucial to invest in research in order to understand the cellular mechanisms at play and prevent risks related to coronavirus epidemics.

 

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