In the ever-evolving landscape of medical treatments, the spotlight is currently on innovative therapies that harness the power of genetics and immunology, particularly in the realm of cancer treatment. While these personalized approaches, such as modified immune cell therapies and targeted antibodies, hold immense promise, they often come with significant complexities and high costs. As a result, they are limited to specific applications and populations. Meanwhile, traditional medical therapies primarily utilize small chemical compounds, which offer a more economical option due to their ability to be produced at scale. However, the significant challenge facing researchers lies in the limited arsenal of new active substances available for development, as current methodologies yield few novel compounds.
A promising solution has emerged from research conducted at Harvard and ETH Zurich in the early 2000s, namely DNA-encoded chemical libraries (DEL). This innovative method has revolutionized the drug discovery process by enabling researchers to generate and evaluate a vast array of chemical compounds efficiently. Initially restricted to the synthesis of smaller molecules, the limitations of early DEL technology became apparent, capping the number of compounds that could be explored. However, recent advancements developed by chemists at ETH Zurich have unlocked new capabilities, allowing for the synthesis of billions of distinct compounds within a matter of weeks. This leap forward enables researchers to explore a much wider chemical space, including the production of larger and more complex drug molecules.
One of the most significant improvements in this refined DEL methodology is its ability to target a broader array of pharmacological sites, including those associated with ring-shaped peptides. According to Jörg Scheuermann, a leading researcher in this field, these developments dramatically expand the horizons of possible active substances. The effective realization of combinatorial chemistry remains the core strategy, facilitating the production of molecular variants by varying the individual building blocks used. As researchers combine various building blocks and cycles of synthesis, the number of potential molecules grows exponentially, leading to a “molecular soup” filled with numerous candidates.
To navigate this complexity, the DEL methodology appends a specific DNA sequence to each compound, acting as an informative barcode. This unique tagging approach allows researchers to isolate and identify the active compounds that exhibit desired efficacy through techniques such as polymerase chain reaction (PCR). Yet, the inherent challenges of linking DNA and chemical building blocks have previously limited the uniqueness and effectiveness of the resulting compounds, leading to redundancy and contamination in molecular libraries.
The ETH Zurich team has addressed these challenges by developing a self-purifying DEL technology that surmounts the contamination issues that plagued earlier efforts. Their innovative process includes linking the synthesis of molecules to magnetic particles, thus facilitating automated handling and washing processes. This method allows for a more focused library, containing only the complete molecules that match the specified DNA code. The experimental implementation was technically demanding, as researchers had to identify magnetic particles that wouldn’t interfere with the enzymatic coupling of DNA.
This self-purifying approach has several key advantages. Aside from managing significantly larger libraries, with the potential to encompass billions of molecules, it also permits the synthesis of larger compounds, including those with five or more building blocks. These larger molecules can interact with diverse protein sites beyond traditional active sites, opening avenues for discovering compounds that influence protein functions in new ways.
The advancements facilitated by this technology are not only pertinent to pharmaceutical development but also have implications for fundamental biological research. The ability to discover molecules that selectively bind to specific protein sites offers new possibilities for protein-labeling and exploration within their native environments. Furthermore, initiatives such as Target 2035 aim to identify molecules for each of the approximately 20,000 human proteins, harnessing the capabilities of the refined DEL technology to influence various biological functions.
To bridge the gap between this groundbreaking technology and its practical application in the industry, Scheuermann’s team is working on establishing a spin-off company. This venture aims to streamline the process from the creation of DEL collections to automated testing and identification, ensuring efficient access for pharmaceutical companies and research teams alike.
As we stand at the cusp of a new era in drug development, the refined DEL technology from ETH Zurich marks a pivotal moment. By transcending previous limitations, researchers are now equipped to explore a broader scope of chemical possibilities that could lead to the next wave of effective medical therapies. As interest from both industry and academia grows, it is evident that the pursuit of novel drugs using this advanced methodology has the potential to transform our approach to treating complex diseases and enhancing human health.