Summary
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.
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.
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More information & hyperlinks
| Web resources: | https://cordis.europa.eu/project/id/706378 |
| Start date: | 07-06-2016 |
| End date: | 06-06-2018 |
| Total budget - Public funding: | 195 454,80 Euro - 195 454,00 Euro |
Cordis data
Original description
Chikungunya virus (CHIKV) is a medically important pathogen that affected millions of people around the world. CHIKVinfection 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.
Status
CLOSEDCall topic
MSCA-IF-2015-EFUpdate Date
28-04-2024
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