Projektbeschreibung
Neuartige Arzneimittel gegen Coronavirus-Infektion
Während der Pandemie erwies sich die Prävention der Infektion mit dem und der Übertragung des SARS-CoV-2 als besonders wichtig. Daher sind neuartige Virostatika erforderlich, die die Bindung von Virionen an Zellen über ihre Spike-Proteine verhindern. Das Projekt Inhibicov wird vom Europäischen Forschungsrat finanziert und stützt sich auf die frühere Identifizierung niedermolekularer Inhibitoren, die möglicherweise gegen alle Coronaviren wirksam sind. Im Rahmen des Projekts werden sich die Forschenden zwei der vielversprechendsten Inhibitoren vornehmen und sie zu klinischen Virostatika weiterentwickeln. Die Verabreichung dieser Arzneimittel soll Krankenhausaufnahmen sowie Sterblichkeitsraten bei Infizierten senken und so die Bevölkerung vor künftigen Coronavirus-Ausbrüchen schützen.
Ziel
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.
Wissenschaftliches Gebiet
- 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
Programm/Programme
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thema/Themen
Finanzierungsplan
HORIZON-AG-LS - HORIZON Lump Sum GrantGastgebende Einrichtung
7610001 Rehovot
Israel