Published in in Journal of Virology: A new mouse model for preclinical evaluation of potential antivirals

As ancestral SARS-CoV-2 viruses are not able to bind to the mouse ACE2 receptor, establishment of SARS-CoV-2 mouse models has been limited to the use of mouse-adapted viruses or genetically modified mice. In parallel, Syrian hamsters are considered one of the best small animal models available for SARS-CoV-2 since SARS-CoV-2 binds efficiently to the hamster ACE2.

Interestingly, some of the variants of concern, such as the Beta B.1.351 variant, show an improved binding to the mouse receptor. The CARE partner KU Leuven (KUL, Belgium) exploited this difference to establish a SARS-CoV-2 Beta B.1.351 variant infection model in an immunodeficient mouse model, i.e., SCID mice, with the aim to develop a robust SARS-CoV-2 mouse infection model for preclinical evaluation of potential antivirals.

The model’s robustness to study the efficacy of small-molecule inhibitors of SARS-CoV-2 infection was confirmed by its sensitivity to molnupiravir or nirmatrelvir and by more efficient replication of the Beta SARS-CoV-2 variant in SCID mice than in wild-type mice.

This SARS-CoV-2 SCID mouse infection model offers an advantage in comparison to other SARS-CoV-2 mouse models – no need to use mouse-adapted virus strains or genetically modified mice – and to the hamster models as it requires lower amounts of drugs, less space, etc..  On the other hand, a limitation is that mice are only susceptible to the Beta variant and that since small-molecule inhibitors should have equipotent activity against all variants, this will be of limited concern for studies with such drugs.

To learn more, click here: A SCID mouse model to evaluate the efficacy of antivirals against SARS-CoV-2 infection

Published in Frontiers in Pharmacology: Combination of antiviral drugs proved to be more efficient than monotherapy

Combinations of antiviral drugs result in improved potency and help to avoid or delay the development of resistant variants in some infectious disease (such as HIV and hepatitis C). From this perspective, CARE partner KU Leuven (KUL, Belgium) explored the potential efficacy of a combination treatment against SARS-CoV-2 variants of concern.

In vitro combination of GS-441524 – a parent nucleoside of remdesivir – and molnupiravir resulted in an overall additive antiviral effect, with a synergism at certain concentrations. Interestingly, co-administration of suboptimal doses of both compound to infected hamsters resulted in a potent antiviral efficacy compared to montherapy.  The combined antiviral activity of drugs having two different mechanisms – molnupiravir induces lethal mutagenesis and GS-441524 terminates RNA transcription prematurely – appears to be highly effective in reducing SARS-CoV-2 replication/infectivity.

The unexpected potent antiviral effect of the combination warrants further exploration as a potential treatment for COVID-19.

To learn more, click here: Combination of the parent analogue of remdesivir (GS-441524) and molnupiravir results in a markedly potent antiviral effect in SARS-CoV-2 infected Syrian hamsters

CARE presentation at ICAR2023

Are you going to ICAR2023 in Lyon in March? If so, you will get the opportunity to hear about a novel SARS-CoV-2 inhibitor discovered and characterized as part of the H2020 project SCORE and IMI project CARE on Wednesday 15 March.

Title of the presentation: A novel SARS-CoV-2 inhibitor with potent activity in a SCID mouse model targets the Membrane protein

Presenter: Manon Laporte

Session Name:  Influenza, RSV, and Other Respiratory Viruses Session

Date/Time:  Wednesday, 15 March, 10:15 am

The faces behind the CARE work-packages – WP7

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 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.  

Quote Card WP7 Maria Vehreschild_V2
Quote Card WP7 Rienk

WP7 – Clinical Evaluation of repurposed or novel SARS-CoV-2 antivirals or antibodies 

The CARE work-package 7 (WP7) aims to clinically evaluate repurposed or novel SARS-CoV-2 antivirals or antibodies through two phase 1 and one phase 2 clinical trials. Maria Vehreschild (Goethe University Frankfurt) and Rienk Pypstra (Pfizer) provided us a short interview with insights into the activities of this work package, its highlights and the challenges that they had to overcome.

How has the collaboration within your WP team developed over the past two years?   

Maria: We have significantly improved our interdisciplinary network within the work package and have gained an in depth understanding of the special expertise of each member.

Rienk: We came to the CARE project with shared goals, but to be most effective in meeting them, we had to get to know each other and the strengths we could all contribute. Over the last two years, we’ve learned many ways in which our diverse technical expertise and experiences are quite complementary.

 

What has surprised you about working on the CARE project?

Maria: Even though we were not able to meet in person over a long period of time, it is impressive how so many experts in their specific fields have still been able to connect and contribute to the entire consortium in a meaningful way.

Rienk: Particularly given how rapidly this public health situation was evolving around the globe, I was impressed with the progress the entire CARE team made to advance activities across workstreams and evaluate assets that could potentially progress into clinical trials.

 

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

Maria: We enjoy working with our international partners and exchanging ideas with them on the challenges that are inherent to the design and conduct of clinical trials.

Rienk: In addition to developing assets that could potentially help fight COVID-19, in CARE we are also laying out a proposed roadmap and infrastructure to help enable a rapid response when subsequent pandemics emerge.

 

What highlights can you share from two years with your WP team so far?

Maria: I truly appreciate the open-minded attitude and communication among the members of our work package.

Rienk: Because our work package focuses on clinical evaluation, our team had to exercise patience while candidates were identified to progress into Phase 1 and Phase 2 clinical trials. But, in the process, we have developed a strong collaborative framework that we believe will further enhance understanding of this disease and approaches to help combat it.

 

What are or were the biggest challenges within WP7? (and how did you overcome them?)

Maria: We are still looking forward to the identification of a drug to be assessed in a clinical trial.

Rienk: One of the biggest challenges for me was balancing the forward-looking preparation required to take assets into clinical development with the uncertainty of not knowing which might be promising enough to advance. We continue to refine this balance every day, as it is the nature of our work.

FAIRplus and CARE collaboration to publish FAIR SARS-CoV-2 data

Publishing datasets in the public domain is important to avoid the duplication of research. For effective dissemination, it is important for the datasets to be FAIR, i.e., Findable, Accessible, Interoperable and Reusable.

The IMI FAIRplus project, whose purpose was to develop tools and guidelines for making life science data FAIR, helped Janssen Pharmaceutica, one of the CARE partners, to improve the FAIRness of a dataset describing the results of ~5,500 FDA-approved drugs and clinical candidates that have passed Phase I studies, which were screened for anti-SARS-CoV-2 activity within CARE. For this purpose, they worked together on the metadata, implemented a standardized ontology and stored data on a long-term hosting platform.

You can now find the dataset on ChEMBL, a publicly accessible repository specifically for bioactive compounds.

To learn more, click here: FAIRplus use case IMI CARE: Quick-response COVID-19 effort opens FAIR data on ~5,500 compounds.

CARE – Infographic – Work Package 7 – Clinical evaluation of repurposed or novel SARS-CoV-2 antivirals or antibodies​​
14 November 2024
CARE – Infographic - Work Package 7 - Clinical evaluation of repurposed or novel SARS-CoV-2 antivirals or antibodies​​ CARE has 8 Work Packages but do you know what each one does? Here, you can learn about the Work Package 7 team, their objectives, their partners, their breakthrough moments and more. The infographic is also available [...]