The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic represents a tragic phenomenon reminding us that new viral pandemics can occur at any time.
Vaccination is the first choice to contain a pandemic, but there are issues related to massive active immunization campaigns, as individual resistance. Moreover, there are categories who cannot be vaccinated or do not respond efficiently to vaccination, e.g., immunosuppressed patients and transplant recipients. Vaccines are also usually expensive and a long time is needed to reach the herd immunity. Finally, their storage and distribution are not always straightforward. Conversely, broad-spectrum antiviral drugs would have the advantages to be outbreak-ready and the possibility to be administered also to people for which vaccination is not recommended.
In recent years, PROteolytic TArgeting Chimeras (PROTACs) technology has emerged as one of the most intriguing approaches in drug design. PROTACs are bifunctional molecules able to induce target protein degradation rather than inhibition and represent a new frontier of pharmaceutical research, with two PROTACs already in phase I clinical trials.
This proposal aims to rationally search new potential molecules based on PROTAC technology against one target of SARS-CoV-2.
Despite the great interest, the use of PROTAC technology is still marginal in the field of antivirals. We will develop small molecule PROTACs targeting the main protease (Mpro). Both the catalytic site and the dimerization surface will be explored as druggable targets, since Mpro is active in its dimeric form. The collaborative work of different research units will guarantee a multidisciplinary approach to develop a starting platform for the development of anti-CoVs agents.
At the end of the research project, we expect to have identified several nontoxic PROTACs molecules endowed with antiviral activity and possibly with high genetic barrier to resistance.
Considering the worldwide mortality rate, hospitalization costs, and the high loss of productivity due to COVID-19 and impact on public health management, as well as the high number of individuals that would benefit from the availability of anti-CoV drugs, the proposed project aims at fulfilling a strong medical need by pursuing the rapid discovery of new therapeutic molecules for COVID-19 but also other CoV-related SARSs by an innovative and multidisciplinary approach. Therefore, this project is expected to have a strong social and economic impact. Differently from vaccines, the availability of anti-CoV drugs will represent a ready-to-use weapon to treat CoV-related SARSs, also for those categories who cannot be vaccinated or do not respond efficiently to vaccination, e.g., immunosuppressed patients and transplant recipients.