The faces behind the CARE work-packages – WP1

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 the 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.  

WP1 – Anti-coronavirus drug discovery in phenotypic virus-cell-based assays 

The CARE work-package 1 (WP1) dedicates its efforts to identify small molecule therapeutic candidates against the current SARS-CoV-2 and potentially other variants of concern using the infectious virus. For this, the CARE scientists take a close look at how the virus can be inhibited in cell culture using drugs that could potentially qualify for repurposing, small molecule libraries and biologicals. The leads of WP1, Ellen van Damme (Janssen) and Pieter Leyssen (KU Leuven) share their view on the work in WP1 of the CARE project. 

What makes the work at CARE special for you and your WP team?  

Ellen: The CARE Consortium has enabled us to pull together experts from across Europe and bring the best minds together to mount an international answer to the challenges that the COVID-19 pandemic presents. By working together and rapidly exchanging information and knowledge, the whole is greater than the sum of its parts. Moreover, our collaboration has given rise to an armamentarium of assays already deployed to benefit consortium academic and industrial partners and beyond. 

How has the collaboration within your team developed over the past year?  

Pieter: During the intense fight against COVID, collaborations have turned into friendships and long-lasting working relationships, which is important to be prepared for future research challenges. 

What has surprised you about working in the CARE project?  

Ellen: Although viruses continue to surprise us with their ingenuity and provide us with challenges, science has come to the point that we can mount a multidisciplinary answer to respond to a pandemic with unseen speed. And yet, the virus keeps taking us by surprise, for example, with the emergence of new variants. 

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 Science Translational Medicine: New cell-free assay 

A CARE research team developed a cell-free assay to quantify neutralizing antibody responses. Neutralizing antibody responses to SARS-CoV-2 are usually assessed using cell-based assays requiring live virus. These assays are time-consuming and necessitate additional biosafety precautions, thus limiting their clinical use. The new cell-free assay can evaluate effective neutralizing antibody responses to SARS-CoV-2 spike protein variants of concern after natural infection and it can be applied to characterize vaccine-induced antibody responses or to assess the potency of monoclonal antibodies.

To learn more, read the paper in Science Translational Medicine: A high-throughput cell- and virus-free assay shows reduced neutralization of SARS-CoV-2 variants by COVID-19 convalescent plasma

CARE paper published in Circulation: Mechanisms of SARS-CoV-2 with regards to endothelial cells

The CARE scientists investigated if the coronavirus infects and damages endothelial cells directly by viral infection or indirectly via neighborhood effects, circulating mediators and immune mechanisms. Endothelial cells build a cell layer that lines blood vessels and regulates exchanges between the blood circulation and surrounding tissues. The generated data indicates that endothelial damage reported in severely ill patients with COVID-19 is more likely secondary to infection of neighboring cells and/or other mechanisms, including immune cells, platelets and complement activation, and circulating proinflammatory cytokines. These findings have implications for therapeutic approaches to tackle vascular damage in severe COVID-19 disease.

To learn more, read the paper in Circulation: Lack of Evidence of Angiotensin-Converting Enzyme 2 Expression and Replicative Infection by SARS-CoV-2 in Human Endothelial Cells