Enzymatisch katalysierte Transformationen sind aufgrund ihrer intrinsisch milden Reaktionsbedingungen für den Aufbau von DELs prädestiniert, wurden in diesem Kontext jedoch bisher einzig für Oligosaccharid-basierte DELs untersucht.
Ziel des Projektes ist die Entwicklung von enzymatischen Strategien zur Synthese von grossen Molekül-Bibliotheken (EnzyDELs). Nach der Identifikation geeigneter Enzyme, werden die Biokatalysatoren mittels Algorithmus-unterstützer gerichteter Evolution für die Anwendung mit DNA-Identifikationscodes optimiert und im Zusammenspiel mit chemischen Reaktionen für die Herstellung von qualitativ hochwertigen Substanz-Bibliotheken genutzt.
Enzymatische Synthese-Strategien können zur Herstellung von qualitativ hochwertigeren und diverseren DNA-kodierten Substanzbibliotheken führen, was die Entwicklung neuer Medikamente, z.B. gegen COVID-19 und verschiedene Krebsarten, signifikant beschleunigen kann.
On March 11th, 2020 WHO Director-General Dr. Tedros Ghebreyesus declared the novel coronavirus (COVID-19) outbreak a global pandemic noting that the WHO is “deeply concerned both by the alarming levels of spread and severity and by the alarming levels of inaction”. As of May 31st, not even three months later, the WHO reported close to 6 million confirmed COVID-19 cases worldwide with more than 350’000 deaths linked to the disease. Apart from the tragic human consequences of the COVID-19 pandemic, few countries will be left unscathed by the coronavirus outbreak’s financial ramifications. The UN predicts that the slowdown in the global economy is likely to cost at least $8.5 trillion leading to a sharp increase in poverty and suffering. The discovery of active pharmaceutical ingredients is a time-consuming process. As a consequence, efforts to implement platforms and tools for the rapid identification and development of drugs against existing and novel disease-relevant targets are of highest priority. While neutralizing antibodies nowadays can be quickly generated, they so far fail for certain viral diseases due to the fast mutation rates of the respective viral coat proteins and additionally are difficult to administer to intracellular targets. This, in principle, could be better achieved with small molecules, however the generation of specific, high-affinity small molecules is a major pharmaceutical challenge.At present, the so-called DNA-encoded chemical library (DEL) technology is considered to be the most powerful method for the discovery of suitable small molecule high-affinity binders4. Building on the idea of Brenner and Lerner to transfer the biological concept of linking phenotype and genotype to the world of small molecules, David Liu (Harvard University) and Dario Neri/ Jörg Scheuermann (ETH Zurich) established the concept of using DNA barcodes to uniquely identify small molecules in large compound collections. In a single test tube, small molecule libraries of up to a billion members have been created and used in affinity-based selection identifying new drug leads.To further advance the powerful DEL technology, the here-proposed project targets to broaden the scope and quality of chemical transformations accessible on DNA by harnessing the catalytic power of enzymes. Enzymes, Nature’s catalysts, function in aqueous media at ambient temperature and are highly specific and tolerant to a wide variety of functional moieties making them ideal tools to build-up molecular diversity in the presence of a DNA strand. Targeting the construction of the pharmaceutically highly relevant C-N bonds through the use of tailored cocktails of natural and engineered imine reductases or a cascade of ATP-dependent CoA ligases and N-acyltransferases, this project will lead to the enzyme-assisted construction of large DEL libraries (EnzyDELs) accessing novel chemical space with increased quality. By carrying out selections against disease-relevant targets such as coronavirus-associated proteins (spike protein and intracellular viral proteins) as well as various tumor-associated antigens (mesothelin, tyrosinase), the novel EnzyDELs will be immediately harnessed in the quest to identify much-needed small molecule drugs.
Last updated:10.06.2022
