ChemProFlav
Financiado
An innovative toolbox based on Pd-catalysis for protease inhibitor synthesis, ap...
An innovative toolbox based on Pd-catalysis for protease inhibitor synthesis, applied to the discovery of pan-anti-flaviviral compounds
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 pe...
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.
ver más
Duración del proyecto: 30 meses
Fecha Inicio: 2022-06-15
Fecha Fin: 2024-12-31
Fecha Fin: 2024-12-31
Línea de financiación: concedida
El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2022-06-15
Línea de financiación objetivo
El proyecto se financió a través de la siguiente ayuda:
HORIZON-MSCA-2021-PF-01-01:
MSCA Postdoctoral Fellowships 2021
Cerrada
hace 3 años
Presupuesto
El presupuesto total del proyecto asciende a
176K€
Líder del proyecto
UNIVERSITEIT ANTWERPEN
No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico
TRL
4-5
Perfil tecnológico
TRL
4-5