Diarylethene-Based Photoswitchable Inhibitors of Serine Proteases
| Autor: | Anne S. Ulrich, Sergii Afonin, Oleg Babii, Jennifer Dommermuth, Andrii Hrebonkin, Alexander Nesterov-Mueller, Christian Diel, Serhii Koniev, Marcel Huhn, Tim Schober, Igor V. Komarov |
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| Rok vydání: | 2021 |
| Předmět: |
Proteases
Serine Proteinase Inhibitors bicyclic peptide Peptide Peptides Cyclic Catalysis Serine chemistry.chemical_compound Diarylethene medicine Animals Serine protease chemistry.chemical_classification biology Bicyclic molecule Photoswitch Molecular Structure Inhibitors Communication General Chemistry Ethylenes Trypsin serine protease inhibitors Combinatorial chemistry hydrogel photoregulation Communications diarylethene photoswitch trypsin chemistry biology.protein Cattle Serine Proteases medicine.drug |
| Zdroj: | Angewandte Chemie (International Ed. in English) |
| ISSN: | 1521-3773 |
| Popis: | A bicyclic peptide scaffold was chemically adapted to generate diarylethene‐based photoswitchable inhibitors of serine protease Bos taurus trypsin 1 (T1). Starting from a prototype molecule—sunflower trypsin inhibitor‐1 (SFTI‐1)—we obtained light‐controllable inhibitors of T1 with Ki in the low nanomolar range, whose activity could be modulated over 20‐fold by irradiation. The inhibitory potency as well as resistance to proteolytic degradation were systematically studied on a series of 17 SFTI‐1 analogues. The hydrogen bond network that stabilizes the structure of inhibitors and possibly the enzyme–inhibitor binding dynamics were affected by isomerization of the photoswitch. The feasibility of manipulating enzyme activity in time and space was demonstrated by controlled digestion of gelatin‐based hydrogel and an antimicrobial peptide BP100‐RW. Finally, our design principles of diarylethene photoswitches are shown to apply also for the development of other serine protease inhibitors. Bicyclic diarylethene‐containing analogues of the sunflower trypsin inhibitor‐1 (SFTI‐1) can modulate activity of serine proteases in the nanomolar–micromolar range in highly efficient photocontrollable manner. |
| Databáze: | OpenAIRE |
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