Billions of new molecules: A quantum leap in drug discovery
ETH Zurich researchers have developed a method to synthesise and test billions of new chemical compounds in weeks, potentially accelerating drug development and expanding the range of treatable conditions.
Amidst the excitement surrounding advanced therapies like personalised cancer treatments, the backbone of modern medicine remains small chemical compounds. These molecules, which can be mass-produced at low cost, form the basis of most medical treatments. However, the discovery of new active substances has long been a bottleneck in drug development. Now, researchers at ETH Zurich have made a significant breakthrough in this field, refining and expanding the capabilities of DNA-encoded chemical libraries (DEL) technology.
The new method, published in the journal Science, [1] allows for the automatic synthesis and testing of billions of different substances within a matter of weeks. This represents a substantial increase from the millions of compounds that could be produced using previous DEL techniques.
Jörg Scheuermann, whose research group at ETH Zurich’s Institute of Pharmaceutical Sciences pioneered this advancement, explained the significance: “The first active substances developed with the help of early DEL technology are currently in advanced clinical trials. This new DEL method once again massively expands the possibilities.”
The power of combinatorial chemistry
At the heart of this breakthrough lies combinatorial chemistry, which aims to produce as many molecular variants as possible from individual building blocks. The number of different molecules grows exponentially with each synthesis cycle and the number of building blocks combined.
To identify active compounds within this vast molecular soup, the DEL method attaches a unique DNA sequence to each molecule, creating a readable barcode for every combination of building blocks. This allows researchers to test the entire collection for specific properties, such as the ability to bind to a particular protein, and then identify promising candidates using PCR techniques.
While the concept of DEL has been around since the early 2000s, its practical application has been limited by chemical realities. The varying effectiveness of chemical linkages between building blocks led to the production of truncated variants, resulting in exponentially increasing impurities with each round of synthesis.
Scheuermann’s team has developed a solution to this problem by introducing a self-purifying mechanism. Their method couples the synthesis of molecules to magnetic particles and incorporates a second chemical coupling component that binds only to the last of the planned building blocks. This allows for the removal of all truncated molecules in a single washing step, ensuring that the final library contains only molecules with all the specified building blocks.
Expanding the scope of drug discovery
The implications of this advancement are far-reaching. Not only does it allow for the handling of much larger libraries of several billion molecules, but it also enables the synthesis of bigger molecules consisting of five or more building blocks.
“Before, we could search for small active substances that fit like a key into the lock of the active site of therapeutically relevant proteins, but now we can search for larger ones as well,” Scheuermann noted. “These larger active substances can dock not only in a protein’s active centres, but also to other specific areas of a protein’s surface, for example, in order to prevent it from binding to a receptor.”
This expanded capability opens up new possibilities for drug development, potentially allowing researchers to target a wider range of proteins and cellular processes.
The new DEL technology is not only poised to accelerate drug discovery but also holds promise for fundamental biological research. By enabling the identification of molecules that bind to specific protein surfaces, it could facilitate the labelling and examination of proteins in their cellular context.
Moreover, this advancement could significantly contribute to major international research initiatives such as Target 2035, [2] which aims to find a specific binding molecule for each of the approximately 20,000 human proteins by 2035.
Bridging the gap between academia and industry
To make this technology widely accessible, Scheuermann and his team plan to establish a spin-off company. This venture will offer a comprehensive service, from the development of DEL collections and automated synthesis to automated efficacy testing and DNA-based identification of molecules.
“We’re seeing immense interest from industry and research, especially in cyclic molecules, which to date haven’t been accessible in large numbers,” Scheuermann said.
As the pharmaceutical industry continues to seek more efficient ways to discover and develop new drugs, this advancement in DEL technology represents a significant step forward. By dramatically expanding the number and types of molecules that can be synthesised and tested, it has the potential to accelerate the drug discovery process and open up new avenues for treating a wide range of diseases.
References:
1. Keller, M., Petrov, D., et. al. (2024). Highly pure DNA-encoded chemical libraries by dual-linker solid-phase synthesis. Science. https://doi.org/10.1126/science.adn3412
2. Target 2035 – www.target2035.net
