Obiettivo Flaviviral infections already represent a threat to 2.5 billion people living in tropical and sub-tropical regions. As a consequence of climate change and global warming in the near future these infections are expected to spread to areas with moderate climate and the possibility of disease outbreak will exist in Europe, especially around the Mediterranean and Adriatic coast, as well as in the United States of America and large parts of Asia. At the moment no medical treatment against flaviviral diseases is available. Recently, peptide-based compounds which act as flaviviral NS3 protease inhibitors, emerged as potent agents against dengue virus (DENV), Zika virus (ZIKV) and West Nile virus (WNV). These compounds consist of two to four natural or unnatural amino acids and act by binding to the active site of the protease. Accordingly, the incorporation of an electrophilic warhead, a moiety which would facilitate the covalent binding of the inhibitor to the catalytic serine residue, into the peptide inhibitor represents a valuable strategy for the improvement of potency of such inhibitors. The goal of the proposed project is to investigate the potential of β-lactams as electrophilic warheads in DENV, ZIKV and WNV protease inhibitors. For that purpose, new β-lactam derivatives will be synthesized, coupled to peptide inhibitors previously developed by the host group and their affinity to the target will be evaluated by biochemical assays. The most potent compounds will be characterized in more detail and their activity against dengue virus replication in cell culture, off-target binding, membrane permeability and metabolic stability will be studied. We expect the formation of a covalent bond between inhibitor and active site of the enzyme to significantly improve inhibitory activity by increasing binding affinity, as well as to ameliorate selectivity and reduce off-target binding. Campo scientifico medical and health sciencesbasic medicinepharmacology and pharmacydrug discoverymedical and health scienceshealth sciencesinfectious diseasesRNA virusesnatural sciencesbiological sciencesmicrobiologyvirologymedical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantibioticsmedical and health sciencesclinical medicineobstetricschildbirth Programma(i) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Argomento(i) MSCA-IF-2016 - Individual Fellowships Invito a presentare proposte H2020-MSCA-IF-2016 Vedi altri progetti per questo bando Meccanismo di finanziamento MSCA-IF-EF-ST - Standard EF Coordinatore RUPRECHT-KARLS-UNIVERSITAET HEIDELBERG Contribution nette de l'UE € 171 460,80 Indirizzo SEMINARSTRASSE 2 69117 Heidelberg Germania Mostra sulla mappa Regione Baden-Württemberg Karlsruhe Heidelberg, Stadtkreis Tipo di attività Higher or Secondary Education Establishments Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Partecipazione a programmi di R&I dell'UE Opens in new window Rete di collaborazione HORIZON Opens in new window Costo totale € 171 460,80