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New-to-nature biocatalysts with metal-substituted proteins

Project description

A green synthesis route for producing high-value pharmaceutical scaffolds

Current chemical manufacturing in the pharmaceutical and agrochemical sectors relies heavily on transition metals to alter complex molecules. However, this multibillion-dollar drug synthesis process is limited by the use of toxic organic solvents and rigid molecular directing groups. Supported by the Marie Skłodowska-Curie Actions programme, the N2BioMetPro project aims to build a bio-based platform that will swap the natural iron core of specific enzymes (non-haem iron enzymes) with cobalt. Researchers will combine computer modelling, machine learning and directed evolution to reshape these artificial metalloenzymes to manipulate their chemical structures with high precision in aqueous environments. This advanced biocatalytic platform should allow scientists to precisely synthesise high-value drug scaffolds.

Objective

Transition-metal-catalysed C–H activation has revolutionised late-stage functionalisation, enabling single-step installation of functional groups into complex molecules and offering superior atom- and step-economy underpinning multibillion-dollar drug syntheses. However, current methods are limited by i) narrow substrate scope, ii) reliance on directing groups for selectivity and iii) organic solvents.
To overcome these limits, N2BioMetPro will build a biocatalytic platform for selective C–H activation by engineering non-haem iron enzymes reconstituted with cobalt (NoHaeCo). Such artificial metalloenzymes merge the catalytic power of organometallic Co(III)-based catalysts with enzymatic advantages: i) aqueous compatibility, ii) mild conditions, iii) precise active-site control and iv) directed evolution strategies to improve selectivity. The N2BioMetPro project pursues two objectives: i) assemble and identify NoHaeCo variants that catalyse abiotic C–H activations, and ii) engineer and evolve their active sites to deliver catalyst-controlled enantio- and regioselectivity, even for substrates without directing groups. Our workflow integrates protein engineering, high-throughput screening, directed evolution, computational modelling and machine learning to obtain efficient, selective NoHaeCo biocatalysts. Target compounds include scaffolds related to Ensartinib, Sebetralstat and Etoricoxib.
This interdisciplinary research combines i) biochemistry, ii) organometallic chemistry, iv) enzymology, and iv) computational science within the Thomas Ward group at the University of Basel, a world leader in artificial metalloenzymes. The fellowship will strengthen my scientific independence and competitiveness, equipping me with cutting-edge skills at the chemistry–biology interface. By advancing catalysis aligned with the European Green Deal, the project will reinforce Europe's leadership in sustainable synthesis for the pharmaceutical, agrochemical and fine-chemical sectors.

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Topic(s)

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HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships

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Call for proposal

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(opens in new window) HORIZON-MSCA-2025-PF

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Coordinator

UNIVERSITAT BASEL
Net EU contribution

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.

€ 292 118,88
Address
PETERSPLATZ 1
4051 Basel
Switzerland

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Region
Schweiz/Suisse/Svizzera Nordwestschweiz Basel-Stadt
Activity type
Higher or Secondary Education Establishments
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Total cost

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