Discovery of potent thrombin inhibitors from a protease-focused DNA-encoded chemical library
| Autor: | Surendra Dawadi, Gabriella Miklossy, Nicholas Simmons, Martin M. Matzuk, Zhifeng Yu, Melek N. Ucisik, Pranavanand Nyshadham, Kurt M. Bohren, John C. Faver |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Proteases
medicine.medical_treatment DNA-encoded chemical library focused DECL Computational biology Chemical library Small Molecule Libraries protease inhibitor chemistry.chemical_compound Thrombin Drug Discovery Catalytic triad medicine Combinatorial Chemistry Techniques Humans Protease Inhibitors Gene Library Multidisciplinary Protease SARS-CoV-2 Chemistry COVID-19 DNA Physical Sciences medicine.drug Discovery and development of direct thrombin inhibitors |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.2005447117 |
| Popis: | Significance To rapidly identify small-molecule lead compounds to target healthcare-associated proteases, we constructed a unique 9.8-million-membered protease-focused DNA-encoded chemical library. Affinity selection of this library with a healthcare-relevant protease (i.e., thrombin, a key protein necessary for blood coagulation) revealed potent inhibitors in the first screening attempt. Our results emphasize the utility of a structurally focused DNA-encoded chemical library approach to rapidly uncover hits for healthcare targets (e.g., proteases) where no drug exists (e.g., male contraception) and for emerging diseases (e.g., coronavirus disease 2019). DNA-encoded chemical libraries are collections of compounds individually coupled to unique DNA tags serving as amplifiable identification barcodes. By bridging split-and-pool combinatorial synthesis with the ligation of unique encoding DNA oligomers, million- to billion-member libraries can be synthesized for use in hundreds of healthcare target screens. Although structural diversity and desirable molecular property ranges generally guide DNA-encoded chemical library design, recent reports have highlighted the utility of focused DNA-encoded chemical libraries that are structurally biased for a class of protein targets. Herein, a protease-focused DNA-encoded chemical library was designed that utilizes chemotypes known to engage conserved catalytic protease residues. The three-cycle library features functional moieties such as guanidine, which interacts strongly with aspartate of the protease catalytic triad, as well as mild electrophiles such as sulfonamide, urea, and carbamate. We developed a DNA-compatible method for guanidinylation of amines and reduction of nitriles. Employing these optimized reactions, we constructed a 9.8-million-membered DNA-encoded chemical library. Affinity selection of the library with thrombin, a common protease, revealed a number of enriched features which ultimately led to the discovery of a 1 nM inhibitor of thrombin. Thus, structurally focused DNA-encoded chemical libraries have tremendous potential to find clinically useful high-affinity hits for the rapid discovery of drugs for targets (e.g., proteases) with essential functions in infectious diseases (e.g., severe acute respiratory syndrome coronavirus 2) and relevant healthcare conditions (e.g., male contraception). |
| Databáze: | OpenAIRE |
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