Acronimo: AC-CURATE

Titolo: Antiviral Compounds against Coronavirus Using pRotAcs TEchnology

Codice Progetto: 20223RYYFC

Responsabile scientifico per il DMM: Prof.ssa Arianna Loregian

Coordinatore: Prof. Gabriele CRUCIANI - Università degli Studi di PERUGIA

Partner-Unità di ricerca: Università degli Studi di PADOVA - Università degli Studi di SIENA - Università degli Studi di ROMA "La Sapienza"

Bando: PRIN 2022 - Decreto Direttoriale n. 104 del 02-02-2022
Durata: 16/10/2023  – 15/10/2025 (24 mesi)

Finanziamento progetto: € 265.545,00 - CUP C53D23004330006

 

Abstract del progetto

Two years after its emergence, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) still represents a public health treat worldwide, reminding us that new viral pandemics can occur at any time. The global society we live in facilitates the progression of viral infection outbreaks into pandemic events and the strategies undertaken to date have not been sufficient to contain the virus. The price being currently paid is very high in terms of both human lives and a global economic and social crisis. Vaccination is the first choice to contain a pandemic and important results have been obtained so far; however, vaccine hesitance, non-durable immunity, and the emergence of more transmissible variants might affect their efficacy. Conversely, broad-spectrum antiviral drugs would have the advantages to be outbreak-ready and could 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 therapeutic approach, with two PROTACs already in phase II and other nine PROTACs investigated in phase I clinical trials. This proposal aims to rationally develop new antivirals based on PROTAC technology against different targets of both SARS-CoV-2 and other pathogenic coronaviruses (CoVs) that might emerge in the future. These antivirals will be developed to have both broad-spectrum anti-CoVs activity and a high barrier to drug resistance. Despite the great interest, the use of PROTAC technology is still marginal in the field of antivirals. Taking advantage of our well-documented experience in the development of antivirals that also act by disrupting protein-protein interactions of viral complexes as well as in the development of successful PROTACs degraders (1-7), we will develop small-molecule PROTACs targeting the main protease (Mpro) and the viral RNA-dependent RNA polymerase (RdRP) nsp12 complex. Regarding Mpro, both the catalytic site and the dimerization surface will be explored as druggable targets, since CoV Mpro is active in its dimeric form. In the case of the RdRP complex, both the catalytic site of nsp12 and the interactions occurring within the nsp12/nsp8 complex will be explored, as this complex is pivotal in viral replication and transcription. The collaborative work of the 4 research units will guarantee a multidisciplinary approach to develop potent anti-panCoV PROTAC candidates in advanced preclinical stage as a starting platform for the development of new anti-CoVs agents.