Development of strategies for high throughput DNA-encoded synthesis of heterocycles, and application to targeting inhibitors of apoptosis proteins (IAPs) as model systems

• Applicants: Professor Dr. Andreas Brunschweiger; Professor Dr.-Ing. Norbert Kockmann
• Subject Area: Biological and Biomimetic Chemistry ; Automation, Mechatronics, Control Systems, Intelligent Technical Systems, Robotics ; Organic Molecular Chemistry - Synthesis and Characterisation ; Pharmacy
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 439638519

The first goal of this research project is the development of a chemically stabilized genetic tag. It shall facilitate a broader scope of methods for designing libraries than the headpiece DNA bar-coding strategy, and a more efficient access to encoded libraries than the hexT approach. The new tagging strategy relies on the literature-known chemical stability of thymine-, cytosine-, and 7-desazaadenine nucleobases to Brønsted and Lewis acids.The second goal is the development of an approach to performing chemistry on chemically stabilized DNA barcodes in organic solvents. A chemically stabilized DNA will be conjugated to a polyethylene glycol polymer to solubilize this molecule in an organic solvent of choice. This strategy shall lead to a new headpiece design that enables a greater scope of reactions due to enhanced DNA stability and the option to perform reactions in organic solvents. Ongoing efforts for on-DNA chemistry on controlled pore glass (CPG) solid phase as previously published, will serve as a back-up plan. The two approaches will be compared in terms of product yields, DNA stability, and operational ease.A collaboration with Prof. Norbert Kockmann, TU Dortmund, takes steps to combine encoded compound library synthesis with laboratory automation and high-throughput experimentation. Optimization campaigns for compound synthesis will be performed with robotic support for dosing and dispension of reagents. The developed synthesis robot platform will be used to further develop DNA-coded chemistry with the opportunity of parallelization of successful synthesis routes. For the solid phase-based approaches, equipment and handling strategies will be designed that allow for repeating synthesis and washing operations in a single well plate. This will open up novel pathways for robust and high-yielding chemical syntheses in encoded library production.The suitability of the chemically stabilized code to synthesize a variety of DNA-tagged target molecules will be tested with methods that were compatible with the TiDEC strategy and through an ongoing collaboration with Prof. Jeffrey Bode to translate so-called SnAP- and OLA-chemistry to an encoded format (ETH Zurich).One library synthesis strategy will then be used to synthesize a proof-of-concept encoded library targeting the Inhibitor of Apoptosis Protein (IAP) family of ubiquitin E3 ligases.

• DFG Programme: Research Grants
• International Connection: Switzerland
• Cooperation Partner: Professor Dr. Jeffery Bode