Objective
Protease inhibitors can potently block the viral replication cycle. In the context of flaviviruses, NS2B-NS3 protease is a promising viral drug target because of its well conserved backbone among flaviviral species, opening the perspective of developing pan-anti-flaviviral NS2B-NS3 inhibitors. All reported NS2B-NS3 inhibitors, however, suffer from low potency and/or poor biopharmaceutical properties. Structural optimization has proven to be slow and challenging, in part because synthetic methodology for fast, chemically versatile and diversity-oriented modification is lacking. To address these challenges, we propose a methodology to assemble protease inhibitors with varying warheads and side chains in just 2 steps from common starting materials, and apply it to the discovery of pan-anti-flaviviral compounds. First, selected amide/carbamate and aldehyde building blocks will be condensed in a reported three-component reaction with phenylsulfinic acid and benzotriazole, delivering individual ‘masked’ N-acylimines. These will be further submitted to innovative cross-coupling steps, in which warheads will be introduced. Once the methodology is optimized and the scope is determined, at least 10 additional analogues of a known NS2B-NS3 inhibitor will be prepared with variations in the warhead, P1 side chain and P2-P3 moieties will be synthesized. They will be subjected to enzymatic affinity determination, binding kinetics analysis and cellular assays. Experimental data will be used to validate a Molecular Dynamics study of NS2B-NS3 inhibitors. The project is envisaged to deliver significant societal, scientific R&I, and economic impacts by managing flavivirus infections and creating business cases for industrial R&I in Europe.
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
MAIN PROGRAMME
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Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) HORIZON-MSCA-2021-PF-01
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
2000 Antwerpen
Belgium
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.