New-to-nature biocatalysts with metal-substituted proteins

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.