Objectif Chikungunya virus (CHIKV) is a medically important pathogen that affected millions of people around the world. CHIKV infection causes high fever, intense joint pain and often leads to chronic virus-induced arthritis, thus there is a clear necessity to develop antiviral compounds capable of eliminating persisting virus. CHIKV is an alphavirus from Togaviridae family with single-stranded positive-sense RNA genome, which replication is carried out by a complex of four viral non-structural (ns) proteins, initially produced in a form of ns-polyprotein precursor and released by proteolytic processing. Because multifunctional nsP2 plays a central role in a replication cycle of CHIKV by exhibiting various enzymatic activities and counteracting cellular defence mechanisms, it represents the most attractive target for drug design and screening. Currently, the structural information regarding CHIKV ns-proteins is limited, whereas the platforms for in vitro testing the potential inhibitors are largely non-existent. Therefore the first aims of this project will be to apply structural biology approaches to elucidate spatial organization of nsP2 and to reveal its contacts with other ns-proteins in the replication complex. The druggability of nsP2 will be then explored by screening recombinant proteins against libraries of chemical fragments and characterizing binding of small molecules using sensitive biophysical techniques and crystallographic analysis. The potential of selected compounds to interfere with enzymatic or interaction properties of nsP2 will be revealed using variety of fluorescence-based assays developed in this project. The newly discovered knowledge about structural features of CHIKV nsP2, identification of novel protein surface pockets and binding molecules, and the development of functional assays for the analysis of their inhibitory potential are expected to create the ground for future elaboration of novel specific inhibitors of CHIKV. Champ scientifique medical and health scienceshealth sciencesinfectious diseasesRNA virusesmedical and health sciencesclinical medicinerheumatologynatural sciencesbiological sciencesmicrobiologyvirologymedical and health sciencesbasic medicinemedicinal chemistrynatural sciencesbiological sciencesbiochemistrybiomoleculesproteins Programme(s) 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 Thème(s) MSCA-IF-2015-EF - Marie Skłodowska-Curie Individual Fellowships (IF-EF) Appel à propositions H2020-MSCA-IF-2015 Voir d’autres projets de cet appel Régime de financement MSCA-IF-EF-ST - Standard EF Coordinateur THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE Contribution nette de l'UE € 195 454,80 Adresse Trinity lane the old schools CB2 1TN Cambridge Royaume-Uni Voir sur la carte Région East of England East Anglia Cambridgeshire CC Type d’activité Higher or Secondary Education Establishments Liens Contacter l’organisation Opens in new window Site web Opens in new window Participation aux programmes de R&I de l'UE Opens in new window Réseau de collaboration HORIZON Opens in new window Coût total € 195 454,80