Pharmaceutical researchers usually find new active substances by searching through many chemical compounds. Chemists at ETH Zurich have made progress in generating and testing these collections using DNA-encoded chemical libraries (DEL).
They use magnetic particles and a self-purification process to create larger molecules. This improved technology could lead to more cost-effective medical treatments based on small chemical compounds.
Developing new molecular therapies has been slow due to the limited number of new active substances found using current methods. A method called DNA-encoded chemical libraries (DEL), developed at Harvard and ETH Zurich, shows promise. While DEL could previously create and test millions of small molecules, ETH Zurich chemists have improved the process.
The new method can produce and test billions of larger molecules, like ring-shaped peptides, in just a few weeks.
“The first active substances from early DEL technology are now in advanced clinical trials. This new DEL method greatly expands the possibilities,” said Jörg Scheuermann, a pioneer in DEL technology at the Institute of Pharmaceutical Sciences.
Combinatorial chemistry aims to create many molecular variants from different building blocks. Researchers then identify the ones that show the desired activity. Different molecules increase exponentially with more synthesis cycles and building blocks.
The DEL method attaches a unique DNA fragment to each chemical building block to identify active molecules, creating a readable barcode for each combination. This allows researchers to test the entire mix’s ability to bind to a specific protein and identify active compounds using PCR.
However, chemical variations can cause the DNA code to lose uniqueness, leading to contamination. This issue has limited DEL libraries to a few million compounds by connecting only three to four blocks.
Scheuermann’s team faced challenges finding magnetic particles that wouldn’t interfere with DNA fragment coupling. Michelle Keller and Dimitar Petrov worked hard to ensure the method worked reliably. Using particles for combinatorial chemistry dates back to the 1990s, but ETH researchers have made it possible.
This self-purifying DEL technology creates more extensive libraries and molecules with five or more building blocks. It enables the search for small active and more extensive substances that can interact with different parts of a protein, preventing it from binding to a receptor.
Finding molecules that can bind to specific protein surfaces benefits fundamental research. This allows scientists to label and study proteins in cells. The ETH method could also help projects like Target 2035, which aims to find a molecule for each of the 20,000 human proteins by 2035.
To make this technology available to industry and researchers, Scheuermann and his team plan to start a spin-off company that will develop DEL collections and offer automated testing and identification of molecules.
Journal reference:
- Keller M, Petrov D, Gloger A, et al., Highly pure DNA-encoded chemical libraries by dual-linker solid-phase synthesis. Science. DOI: 10.1126/science.adn3412.
- Satz, A.L., Brunschweiger, A., Flanagan, M.E. et al. DNA-encoded chemical libraries. Nature Reviews Methods Primers. DOI: 10.1038/s43586-021-00084-5.
- Keller M, Schira K, Scheuermann J (2022). Impact of DNA-Encoded Chemical Library Technology on Drug Discovery. Chimia, DOI: 10.2533/chimia.2022.388.
