Descrizione del progetto
Nuovi farmaci contro i coronavirus
La prevenzione efficace dell’infezione e della trasmissione della SARS-CoV-2 è emersa quale priorità chiave nel corso della pandemia. Servono pertanto nuovi farmaci antivirali in grado di impedire ai virioni di attaccarsi alle cellule per mezzo delle loro proteine spike. Il progetto Inhibicov, finanziato dal Consiglio europeo della ricerca, sfrutta i risultati ottenuti in passato dall’individuazione di piccoli inibitori di molecole che dispongono del potenziale di agire contro tutti i coronavirus. Nel corso del progetto i ricercatori prenderanno in esame due de più promettenti di questi inibitori per svilupparli ulteriormente, sino a renderli farmaci antivirali a uso clinico. La somministrazione di questi farmaci dovrebbe ridurre i ricoveri ospedalieri e la mortalità nei pazienti infetti, salvaguardando le popolazioni da possibili future epidemie di coronavirus.
Obiettivo
The Covid-19 pandemic emphasized the urgent need for efficient broad-spectrum antiviral drugs against potential future coronaviruses (CoV) strains that may cause the next COVID pandemic. A critical stage during infection is the fusion of the viral envelope with the host-cell membrane, which depends on the conserved S2 domain of the viral Spike (S) protein. Hence, targeting the S2 domain is a promising approach to achieving pan-CoV inhibition. Since MERS- and SARS- S proteins bind to different cellsurface receptors through the rapidly diversifying S1 domain, we reasoned that compounds that inhibit both must target the S2 domain. We developed and performed a robust fluorescence-based high-throughput screen of 173,227 unique compounds and classified them based on their ability to inhibit infection of pseudoviruses bearing either MERS or SARS-2 S proteins at single-cell resolution. To our knowledge, this is the largest screen performed to date. This analysis identified several potent broad-spectrum small molecules that inhibit S protein mediated infection at sub-micromolar concentrations. Moreover, the compounds we discovered obey Lipinski's rule of five, indicating that they can potentially become drugs to prevent viral transmission.
This project aims to develop two of the most promising broad-spectrum CoV small molecule inhibitors to create more clinically ready compounds with up to 100% inhibition activity that could be administered orally to reduce hospitalizations, prevent chronic effects, and reduce mortality. The technical work in the project is focused on lead optimization leading towards broad-spectrum antiviral drugs against future outbreaks of bat-borne viruses. The project also comprises pre-commercialization activities, where IP protection and commercialization planning are the core activities. Eventually, we will expect our developed compound(s) to boost the market for antiviral therapies for bat-borne viruses.
Campo scientifico
- natural sciencesbiological sciencesmicrobiologyvirology
- medical and health scienceshealth sciencespublic healthepidemiologypandemics
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- medical and health scienceshealth sciencesinfectious diseasesRNA virusescoronaviruses
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantivirals
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
HORIZON-AG-LS - HORIZON Lump Sum GrantIstituzione ospitante
7610001 Rehovot
Israele