Arianna Loregian

ARREST-COV: AntiviRal PROTAC-Enhanced Small-molecule Therapeutics against COronaViruses

Required budget: 30.000 euro

With this project, our research group, which has many years of experience in the development of new antivirals – including molecules against respiratory pathogens such as the influenza virus and the MERS-Coronavirus, aims at identifying compounds with activity against the new Coronavirus called SARS-CoV-2.

To develop new anti-SARS-CoV-2 drugs we will use 3 different strategies in parallel: 1) drug repurposing, i.e., the identification of drugs that are already in clinical use against other diseases and are endowed with activity also against SARS-CoV-2 (an approach that has already been used to discover the anti-SARS-CoV-2 activity of remdesivir, a drug previously developed against the Ebola virus); 2) large-scale screening of libraries of millions of compounds against the SARS-CoV-2 protease 3CLpro, an enzyme with a key role in viral replication; 3) the development of inhibitors of interactions between proteins of the SARS-CoV-2 replication complex (a strategy that our research group has already successfully used to identify new anti-influenza compounds, which have been published and patented). In particular, we intend to target interaction regions between viral proteins that are highly conserved in Coronaviruses, in order to develop compounds active against SARS-CoV-2 but also against other Coronaviruses of animal origin that could emerge in the future.

Furthermore, thanks to the collaboration with a group of chemists from the University of Perugia, we intend to enhance the antiviral activity of the compounds identified with the various strategies by exploiting an innovative technology based on PROTAC (PROteolytic TArgeting Chimeras). This technology allows obtaining, in addition to the specific inhibition, also the degradation of the viral target. The main advantage of this pharmaceutical enhancement is that, even if the binding affinity of the inhibitor with the viral target is initially low, thanks to the PROTAC technology its potency can be increased by up to 1000 fold.

At the conclusion of this multidisciplinary project, we expect to have identified various molecules with potent activity against SARS-CoV-2 but also with activity against other highly pathogenic Coronaviruses, in order to have potential weapons against possible other Coronaviruses of animal origin that could emerge in the future and cause other devastating epidemics or pandemics worldwide.

Arianna Loregian

ARREST-COV: AntiviRal PROTAC-Enhanced Small-molecule Therapeutics against COronaViruses

Required budget: 30.000 euro

With this project, our research group, which has many years of experience in the development of new antivirals – including molecules against respiratory pathogens such as the influenza virus and the MERS-Coronavirus, aims at identifying compounds with activity against the new Coronavirus called SARS-CoV-2.

To develop new anti-SARS-CoV-2 drugs we will use 3 different strategies in parallel: 1) drug repurposing, i.e., the identification of drugs that are already in clinical use against other diseases and are endowed with activity also against SARS-CoV-2 (an approach that has already been used to discover the anti-SARS-CoV-2 activity of remdesivir, a drug previously developed against the Ebola virus); 2) large-scale screening of libraries of millions of compounds against the SARS-CoV-2 protease 3CLpro, an enzyme with a key role in viral replication; 3) the development of inhibitors of interactions between proteins of the SARS-CoV-2 replication complex (a strategy that our research group has already successfully used to identify new anti-influenza compounds, which have been published and patented). In particular, we intend to target interaction regions between viral proteins that are highly conserved in Coronaviruses, in order to develop compounds active against SARS-CoV-2 but also against other Coronaviruses of animal origin that could emerge in the future.

Furthermore, thanks to the collaboration with a group of chemists from the University of Perugia, we intend to enhance the antiviral activity of the compounds identified with the various strategies by exploiting an innovative technology based on PROTAC (PROteolytic TArgeting Chimeras). This technology allows obtaining, in addition to the specific inhibition, also the degradation of the viral target. The main advantage of this pharmaceutical enhancement is that, even if the binding affinity of the inhibitor with the viral target is initially low, thanks to the PROTAC technology its potency can be increased by up to 1000 fold.

At the conclusion of this multidisciplinary project, we expect to have identified various molecules with potent activity against SARS-CoV-2 but also with activity against other highly pathogenic Coronaviruses, in order to have potential weapons against possible other Coronaviruses of animal origin that could emerge in the future and cause other devastating epidemics or pandemics worldwide.