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CARE presentation at 19th Annual PEGS Boston conference and expo

Are you going to the 19th Annual PEGS Boston conference & Expo: The Essential Protein Engineering and Cell Therapy Summit next week? If so, you will have the opportunity to discover how to identify pre-lead antibodies that have multiple epitopes on the SARS-CoV-2 spike protein using Carterra’s high-throughput epitope binning. Do not hesitate to visit the poster by CARE partner Takeda during one of the Poster Viewing session.

Title of the presentation: Identification of Binning Diversity and Binding Properties of SARS-CoV-2 Antibodies Using Carterra

Presenter: Hazal B. Kose, Ruiyang Xuee

Published in Antiviral Res: A VeroE6 cell line not requiring Pgp inhibitors to evaluate SARS-CoV-2 antivirals

Cell culture virus replication systems are essential for the study of virus replication and pathogenesis, antiviral drug testing, and virus research. Vero cells are one of the cell lines used for drug discovery as they are susceptible to SARS-CoV-2 infection – as well as to SARS-CoV-1 and MERS viruses -, easy to maintain, offer high levels of infectivity, and support efficient SARS-CoV-2 replication and virus production.

However, Vero cells express high levels of multidrug resistance protein 1 (MDR1), also named Pgp (P-glycoprotein), an ATP-dependent efflux pump, which necessitates the inclusion of a Pgp inhibitor in the cell culture to prevent tested compounds from being exported out of cells, affecting the antiviral activity as well as interpretation of data. To address this, CARE partner Pfizer used gene editing technology to generate a Pgp gene knockout VeroE6 cell line.

The VeroE6-Pgp-KO cells no longer expressed the Pgp protein and show significantly reduced efflux transporter activity. When remdesivir and nirmatrevil, two known Pgp substrates, were tested in this cell line, both drugs showed antiviral activities similar to that observed in the presence of the Pgp inhibitor.

This newly established VeroE6-Pgp-KO cell line adds a new in vitro virus infection system for SARS-CoV-2 – and possibly other viruses – to test antiviral therapies without a need to control the Pgp activity, and thus with less data variation and failed assays.

To learn more, click here: Generation of a VeroE6 Pgp gene knock out cell line and its use in SARS-CoV-2 antiviral study

Published in iScience: A new  optimized SARS-CoV-2 phenotypic screening platform

The CARE partner Goethe University Frankfurt Institute of Medical Virology, published a paper reporting on a novel phenotypic screening platform for the identification of drug candidates with activity against SARS-CoV-2 and other coronaviruses. This successful proof of concept was based on the determination of caspase 3/7 activity using the one-step Caspase-Glo 3/7 Assay System as readout. This platform uses the Caco-2-F03 cell line which demonstrated susceptibility to a broad range of SARS-CoV-2 without being affected by phospholipidosis, a known cause of false-positive hits, and is also considered suitable for neutralisation assays and phenotypic resistance testing.

To learn more, click here: Identification of novel antiviral drug candidates using an optimized SARS-CoV-2 phenotypic screening platform

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 6th and final External Newsletter is now available
20 March 2025
CARE External Newsletter - March 2025 The final issue of our biannual newsletter is out. In this edition we share CARE’s legacy: key outcomes resulting from CARE’s five-year endeavours; a report from the recent CARE Annual Meeting in Paris; CARE’s recently published White Paper* and final Infographic as well as lLinks to all CARE news [...]