CARE paper published in Antiviral Research: Insight on the activity of Remdesivir, Molnupiravir and Nirmatrelvir on SARS-CoV-2 variants of concern

The CARE partner KU Leuven, in collaboration with University Hospitals Leuven evaluated the susceptibility of SARS-CoV-2 variants   to Remdesivir, Molnupiravir and Nirmatrelvir. The three molecules have in vitro antiviral activities against the ancestral virus as well as the alpha, beta, gamma, delta and omicron variants. This indicates that the target genes of these antivirals are highly conserved between SARS-CoV-2 variants.

To learn more, read the paper in Antiviral Research: Remdesivir, Molnupiravir and Nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern

CARE paper published in Journal of Medical Virology: Development and optimization of a high-throughput screening assay for in vitro anti-SARS-CoV-2 activity

The CARE partners KU Leuven and Janssen Pharmaceutica NV, in collaboration with The Institute of Medical Virology published a paper reporting on the outcomes from screening a library of antiviral compounds to assess effectiveness against SARS-CoV-2 as part of the emergency response to the pandemic. Although vaccines are currently used to control the COVID-19 pandemic, treatment options are urgently needed for those who cannot be vaccinated and for future coronavirus outbreaks. A high-throughput, high content imaging–based SARS-CoV-2 infection assay was developed and used to screen a library of 5676 compounds that passed Phase 1 clinical trials. Eight drugs were identified as inhibitors of in vitro anti–SARS-CoV-2 activity. However, apart from remdesivir, toxicity and pharmacokinetic data did not support further clinical development of these compounds for COVID-19 treatment.

To learn more, read the paper in the Journal of Medical Virology:: Development and optimization of a high-throughput screening assay for in vitro anti-SARS-CoV-2 activity: Evaluation of 5676 Phase 1 Passed Structures

High throughput cryo-electron microscopy epitope mapping of SARS-CoV-2 spike protein antibodies

The CARE partners Takeda and Utrecht University, in collaboration with Thermo Fisher Scientific, published a white paper demonstrating how cryo-electron microscopy can be used as tool for high-throughput epitope mapping of antibodies that block SARS-CoV-2 virus entry. One of the main concerns of the ongoing COVID-19 pandemic is SARS-CoV-2 variants that may be able to evade immunity. Epitope mapping of large antibody panels allows researchers to identify vulnerable sites on the spike protein, predict and interpret the effect of new mutations, and speed up decision-making in selecting antibody combinations that target non-overlapping epitopes. The results show how an optimized sample preparation workflow and state-of-the-art data technology can be used to expedite antibody drug discovery, which is of great importance for COVID-19 and future pandemic threats.

To learn more, click here: High-throughput cryo-EM epitope mapping of SARS- CoV-2 spike protein antibodies using EPU Multigrid

Published in Nature Communications: Mechanism of AT-527 presents as a promising research avenue against COVID-19

A research group including the CARE partner Aix-Marseille University investigated the guanosine analogue AT-527 (Bemnifobuvir) using high-resolution cryo-electromicroscopy. Once in cells, AT-527 is converted into AT-9010that presumably has a dual mechanism of action (1) at the level of the viral RNA-dependent RNA polymerase which enables incorporation into the viral RNA, stopping the synthesis of viral genomes, and (2) at the N-terminal domain of nsp12 where it inhibits the activity of nucleotidyltransferase, an enzyme that transfers a nucleotide from one structure to another. The dual mechanism represents a promising research avenue against COVID-19 and the detailed findings are published in Nature Communications.

To learn more, read the paper in Nature Communications: A dual mechanism of action of AT-527 against SARS-CoV-2 polymerase

The faces behind the CARE work-packages – WP3

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.  

WP3_QuoteCard_Chaltin

WP3 – Hits to leads 

The CARE work-package 3 (WP3) aims to identify and optimize small molecule antiviral drug candidates that are suitable for preclinical and clinical evaluation. The WP also assesses the impact of small molecule research and development decisions on the downstream health system and has a strong focus on pandemic preparedness as well as outbreak response. Patrick Chaltin (Centre for Drug Design and Discovery (CD3), KU Leuven), the lead of WP3 provides more insights into the work-package activities and the challenges he and his team had to overcome.

 

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

Being part of the CARE consortium, which brings together top academic research groups, biotech and pharma companies with expertise in virology and/or drug discovery and development, allows our teams to make a significant contribution to the battle against the current global pandemic. We are working together in a really unique setting, aiming to combine the strengths of all CARE partners with the same goal – this is very motivating and exciting!

 

What are or were the biggest challenges within your WP? And how did you overcome them?

As the consortium consists of many partners and was established in a crisis situation, the identification of the various available assays, resources, and especially the ongoing hit identification required significant effort. A regular exchange between the WPs 1, 2 and 3 allowed us to get accurate status updates. It seemed that not many starting points were available at the start of the project, so we focused a part of our initial efforts on supporting the hit identification in WP1 and WP2. Streamlining and prioritizing many different approaches was a second challenge at that time. The implementation of fully empowered drug discovery teams focusing on the different targets and approaches ensured the required flexibility for the teams to move ahead in the most efficient way depending on the needs of the specific approach. This enables the implementation of dedicated streamlined screening cascades for each approach with input from other WPs. Open discussions as well as exchange of compounds and results with partners of the WPs 1 and 2 ascertain the prioritization of the most promising hit matter and a focus on the hit to lead programs with the highest potential.

 

What are your expectations and wishes for the future?

Our main expectation is that we will identify at least one potent (broad-spectrum) SARS-CoV antiviral candidate drug which can be further developed and helps to control the current SARS-CoV-2 pandemic and potential future variants or outbreaks of the coronavirus. Also, the CARE consortium is a great project to demonstrate that various teams with different backgrounds from academia, biotech and the pharma industry and their different interests can work together and achieve great outcomes.

CARE paper published in Antiviral Research: Insight on the activity of Remdesivir, Molnupiravir and Nirmatrelvir on SARS-CoV-2 variants of concern

31 May 2022
CARE paper published in Antiviral Research: Insight on the activity of Remdesivir, Molnupiravir and Nirmatrelvir on SARS-CoV-2 variants of concern The CARE partner KU Leuven, in collaboration with University Hospitals Leuven evaluated the susceptibility of SARS-CoV-2 variants   to Remdesivir, Molnupiravir and Nirmatrelvir. The three molecules have in vitro antiviral activities against the ancestral virus as [...]