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Financement de l’UE (175 920 €) : Une boîte à outils innovante basée sur la catalyse pour la synthèse d’inhibiteurs de protéase, appliquée à la découverte de composés pan-anti-flaviviraux Hor20/06/2022 Programme de recherche et d'innovation de l'UE « Horizon »
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Une boîte à outils innovante basée sur la catalyse pour la synthèse d’inhibiteurs de protéase, appliquée à la découverte de composés pan-anti-flaviviraux
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.
| Katholieke Universiteit Leuven | ? |
| Universiteit Antwerpen | 175 920 € |
https://cordis.europa.eu/project/id/101069018
Cette annonce se réfère à une date antérieure et ne reflète pas nécessairement l’état actuel. L’état actuel est présenté à la page suivante : Katholieke Universiteit te Leuven, Leuven, Belgique.
