The faces behind the CARE work-packages – WP2

CARE (Corona Accelerated R&D in Europe) is the largest European research initiative addressing the challenges of COVID-19. It is no surprise that it is designed in a comprehensive, yet agile, structure to fulfill the 37 partners’ shared key goals: (1) to identify therapeutics for the current pandemic, (2) to identify antiviral therapies for future outbreaks and (3) to increase the understanding of the pathophysiology of COVID-19. In a set-up of eight work-packages (WPs), the scientists and management at CARE carry out the project activities that have so far resulted in valuable learnings about COVID-19 and how it might be defeated.  

In this monthly series, we go behind the scenes through brief interviews with the leadership of each of the eight CARE work-packages to hear insights on what makes their work so special, as well as their challenges and hopes.  

WP2 – Target-based drug discovery and design 

The CARE work-package 2 (WP2) is tasked with the identification of novel small molecule therapeutic candidates against the current the SARS-CoV-2 virus by conducting target-based drug discovery and design. The leads of WP2, Bruno Canard (Aix-Marseille University) and Kumar Saikatendu (Takeda) provided us in a short interview with insights into this research area, and talked about focal points, projects, challenges, and wishes for the future.

WP2 focuses on experimental target-based and in silico artificial intelligence (AI)-based screening and profiling of potentially novel compounds against SARS-CoV-2. What is special about this approach?  

Kumar: This program is a test bed of many newly emerging technologies. Especially tremendous advances made in the field of artificial intelligence and machine learning are helping us find new hits quickly. These are then being tested rapidly in actual assays within WP2

What are or were the biggest challenges within WP2? (and how did you overcome them?)

Bruno: There are technical challenges because protein purification is often unpredictable and sometimes resemble to an art: although you design and follow protocols, the devil is in the detail. Sometimes a single amino-acid change in a protein alters a well-defined process. The skills, experience, and intuition of our technicians and engineers are key, and they play an essential role inside the project. Their work facilitated the transmission, exchange, and discussion of ideas inside the consortium. The second challenge is to make all these different corporate and academic partners work together, with the common goal of advancing science and solutions to control the pandemic. It takes a lot of administrative effort to coordinate such a huge and diverse effort. I am grateful to our restless scientific and administrative managers for addressing so many complicated yet essential issues. Overcoming these challenges is a relentless effort made of discussions, interactions, meetings and finding the right balance to be physically present and available in the lab. During the intense fight against COVID, collaborations have turned into friendships and long-lasting relationships for future research.

What are important interfaces with the other CARE work-packages?

Kumar: The main interfaces are both upstream and downstream of WP2. Validated hits emerging from WP2 need to be further profiled upstream in the WP1 virology assays and get initial data on SARS-CoV-2 neutralization. Secondly, downstream in WP3, the medicinal chemistry teams are well prepared to optimize these hits into potent inhibitors. This integration of WP1, 2 and 3 is of paramount importance to the success of IMI-CARE.

What are your expectations and wishes for the future?

Bruno: Part of my expectations are already fulfilled: Awareness of the need for a scientific preparedness towards emerging viruses will never be the same. What has been achieved up to now is truly remarkable in terms of knowledge, speed, and conquest of public opinion. When I started working on viruses two decades ago, people thought I was working on computer viruses. Now, almost everyone on earth knows what the coronavirus spike is. Education of the general public has made an incredible leap forward, and I believe that they understand that the present crisis is also an opportunity to implement better sustainable practices on our planet, as well as be better prepared to react efficiently and promptly to pandemics. The role of science and its interconnection between academia and industry is increasingly considered vital. The general public is also learning the difference between research, with its debates and conflicts, and its consensus product, science. My wish is that IMI-CARE will further contribute to these positive evolutions of our societies.

CARE paper published in JCIM: Modeling of protein-small molecule complexes with HADDOCK

CARE partners of the University of Utrecht studied the interactions between compounds and protein receptors using a new protocol in HADDOCK (High Ambiguity Driven DOCKing). Compound-protein interactions are a crucial task in drug discovery and HADDOCK is an integrative modeling platform which incorporates homology information for both, compounds and protein receptors. The protocol developed with HADDOCK incorporates all the lessons that the research team has learned over 3 years. Ultimately, the scientists developed two protocols and benchmarked their performance.

To learn more, read the paper in Journal of Chemical Information and Modeling: Shape-Restrained Modeling of Protein-Small Molecule Complexes with High Ambiguity Driven DOCKing

CARE paper published in Journal of Virology: New insights for assessment of SARS-CoV-2 infection estimates and (vaccine-induced) antibody durability response 

CARE researchers have determined SARS-CoV-2-specific antibody responses to different proteins (trimeric spike protein, monomeric spike protein and nucleocapsid protein) in sera of people infected with COVID-19 in acute-infection and post-infection phases. The results suggest that in order to generate correct estimates of SARS-CoV-2 infections in the general population, it is better to test for a specific type of antibody response, i.e. the antibodies that are generated in response to the trimeric spike protein as opposed to the monomeric spike protein and the nucleocapsid protein. Furthermore, the assessment of antibody responses against the trimeric spike protein will be critical to evaluate the durability of the antibody response for the characterization of a vaccine-induced antibody response.

To learn more, read the paper in the Journal of Virology: Changes in SARS-CoV-2 Spike versus Nucleoprotein Antibody Responses Impact the Estimates of Infections in Population-Based Seroprevalence Studies

CARE paper published in iScience: CD177 is associated with coronavirus disease severity 

In an effort to increase the understanding of SARS-CoV-2, CARE researchers found that the activation of a type of white blood cells called neutrophils could be linked to the overexpression of a protein encoded by the CD177 gene. They concluded that CD177 is a reliable prognostic marker for routine care.

To learn more, read the paper in iScience: CD177, a specific marker of neutrophil activation, is associated with coronavirus disease 2019 severity and death

CARE paper published in Nature: HCQ use against SARS-CoV-2 infection

CARE scientists demonstrated that there is no definitive evidence that Hydroxychloroquine (HCQ), whether alone or in combination with azithromycin, is effective for treating COVID-19. The investigation was part of CARE’s efforts to evaluate the efficacy of repurposed drugs.

To learn more, read the paper in Nature: Hydroxychloroquine use against SARS-CoV-2 infection in non-human primates