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Modern approaches for developing antivirals against SARS-CoV 2

Periodic Reporting for period 1 - MAD-CoV 2 (Modern approaches for developing antivirals against SARS-CoV 2)

Reporting period: 2020-08-01 to 2021-07-31

The MAD-CoV 2 project is a collaboration of world-leading researchers and innovative industry partners that aims to develop and deliver treatment for COVID-19 patients, significantly increasing the capacity to handle the current outbreak of SARS-CoV-2. Additionally, this project will also identify and characterize new targets for the development of antiviral therapeutics by using state-of-the-art technology.
The general objectives has been, i) to establish state-of-the-art infection model system; ii) to verify the antiviral activity of recombinant soluble human Angiotensin-converting enzyme 2 (srhACE-2), iii) to identify and characterize new essential host cell factors for SARS-CoV-2 and other Corona viruses with pandemic potential, iv) to develop novel antiviral therapies to target novel host factor essential for SARS-CoV-2 infections, v) to exploit project outputs and disseminate the results to the scientific community, public health bodies, NGOs, outbreak management teams.

The general concept of the project has been to address the objectives by two different approaches;
1- The fast track: Demonstrating that GMP clinical grade soluble recombinant human ACE2 (srhACE2) ameliorates SARS-CoV-2 infections, (ACE2 being the receptor of SARS-CoV-2)
2- The innovative track: Identifying and exploiting novel therapeutic targets using unique high-throughput mutagenesis screens.
Within WP1, the management and coordination of MAD-CoV 2 has been organised around a Project Management Team (PMT), composed of two partners (SVA and IT) and whose role is, to act as the interface between the consortium and the IMI office, to hold the accounting of the project, to ensure that project deliverables and reports are timely submitted to the IMI offices, to organize the General Assembly (GA) and Executive Committee (ExCom) meetings, drafting the agenda and minutes of these meetings.
In period 1 the management tools and templates for the scientific as well as for the financial monitoring of the project have been set up. The monitoring of the work progress has started with regular updates delivered by the WP leaders during project meetings. The Kick-off meeting and 3 ExCom meetings have been organized.

Within WP2 the aim is to verify the antiviral activity of recombinant soluble human Angiotensin-converting enzyme 2 (srhACE-2). In period 1, we have demonstrated that srhACE-2 inhibits SARS-CoV2 infection 1000-5000 times. We have also demonstrated that srhACE-2 can increase the antiviral activities of remidisivir in a combination therapy using in vitro systems.

Within WP3, our forward genetic screening approaches have already been applied to further understand the cellular mechanism of the antiviral Remdesivir (Monteil et al., EMBO Mol Med 2021) and will now be used to find novel host cell factors required for SARS-CoV-2 infection and replication. Within the first period, the specialized haploid cell systems were equipped with the SARS-CoV-2 entry receptor ACE2, which renders these cells susceptible to SARS-CoV-2 infection and enables our screens for essential host cell factors in the next project period.
We further identified sugar binding proteins (lectins) that directly interact with SARS-CoV-2 spike protein and partially prevent the interaction with host cell surfaces (Hoffmann and Mereiter et al., EMBO 2021). Such lectins could therefore be potent tools to prevent SARS-CoV-2 cell entry.

Within WP4, partner JLU is working on a transcription repressor that was published to be an important SARS-CoV-2 host cell factor (Daniloski et al., Cell 2021, DOI: 10.1016/j.cell.2020.10.030).JLU also participated in an in silico screen for SARS-CoV-2 host cell factors that led to the identification of 2 approved drugs that are able to inhibit the virus (Han et al., Science Advances 2021, DOI: 10.1126/sciadv.abh3032).

Within WP5, IT has prepared the project website, and the project communication pack. Furthermore, partner IBEC has been in charge to supervise MAD-CoV 2 Virtual Reality video and mobile app. Both dissemination tools were delivered by the expected time (31/07/2021). MAD-CoV 2 activity has been disseminated to the general public in the framework of the second City and Science Biennial of Barcelona (8th-13th June 2021) counting with IBEC partner as curator of dozens of activities during the Biennial. The talks were held in front of scholars (age of 12-14 years), general public, and scientists using different formats (public agora, round tables and scientific talk) targeting a wide range of social groups. Of note, part of the results of MAD-CoV 2 were shared in a round table counting with the participation of IBEC(Nuria Montserrat) and the Nobel Prize for Peace Ernest Kahan in the framework of the City and Science Biennial of Barcelona. Overall, in the City and Science Biennial of Barcelona we were able to promote awareness and preparedness to pathogen outbreaks also stressing the support from IMI to tackle them.
MAD-CoV 2 has targeted two dimension of this call. This initiative will bring evidence that srhACE can be used for antiviral treatment already for this current outbreak, thanks to the access to GMP srhACE2 through a well establish SME with capacity to provide the product for clinical trials and beyond. By using 3D organoid model system as validation system for identified host cell target, this initiative has contributed to increase the knowledge on molecular pathogenesis of SARS-CoV-2. The 3D organoid infection model will give us, and other scientists, tools for investigating the molecular pathogenesis of the pathogens and also can be used as a validation model for antivirals. In addition, we have also, through our state-of-art haploid cell screening, been able to identify a resistance mechanism for remdesivir.
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