OASS Covalent Inhibitors

Design and synthesis of mechanism based O-acetylserine sulfhydrylase inhibitors (WP 2)

Dr. Aigars Jirgensons
Latvian Institute of Organic Synthesis

Availability of cysteine is crucial for bacteria since this amino acid is the preferential source of sulfur for all sulfur-containing biological molecules, such as methionine, biotin, thiamin and iron–sulfur clusters. The final two steps of cysteine biosynthesis in the sulfur assimilation pathway are carried out by serine acetyl transferase (SAT) and O-acetylserine sulfhydrylase (OASS). By following preliminary results, we will focus on design and synthesis of novel series of chemo-types, active towards the two OASS isoforms of Gram-negative bacteria, specifically S. typhimurium, exploiting the active site geometry and the coenzyme reactivity. We will also investigate the catalytic and regulatory properties of SAT as a prerequisite for the identification of selective inhibitors. The inhibitors will be used to assess the druggability of these enzymes as Gram-negative antibacterial agent target. Our final goal, given that cysteine acts as feedback inhibitor of SAT is the design of dual-specific ligands for SAT and OASS. To discover novel inhibitors for the enzymes of bacterial sulfur metabolism, we will synthesise mechanism based inhibitors of OASS-A and OASS-B by exploiting the reactivity of coenzyme PLP.

Objectives: To develop mechanism based covalent inhibitors of OASS that can be used as tool compounds to investigate the role of OASS as antibacterial targets. These inhibitors serve as lead compounds for antibacterial drug discovery.

Expected Results: Novel inhibitors of OASS. Novel methods for the synthesis of unnatural amino acids.

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This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska Curie grant agreement No  642620
European Union