Design and Synthesis of Metabolically Stable tRNA Synthetase Inhibitors Derived from Cladosporin
| Autor: | Esther K. Schmitt, Christian Studer, Patrick Rollin, Madeleine Livendahl, Beatrice Ranieri, Marion Rusch, Carsten Spanka, Arnaud Thevenon, Thomas Aust, Maude Patoor, Laure C. Bouchez, Karl Gademann, Dominic Hoepfner |
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| Rok vydání: | 2019 |
| Předmět: |
Lysine-tRNA Ligase
Plasmodium falciparum 010402 general chemistry 01 natural sciences Biochemistry Antimalarials Structure-Activity Relationship Drug Discovery Humans Potency Antimalarial Agent Enzyme Inhibitors Malaria Falciparum Molecular Biology chemistry.chemical_classification biology 010405 organic chemistry Chemistry Drug discovery Organic Chemistry biology.organism_classification 0104 chemical sciences Bioavailability Enzyme Isocoumarins Transfer RNA Molecular Medicine Cladosporin |
| Zdroj: | ChemBioChem. |
| ISSN: | 1439-7633 1439-4227 |
| DOI: | 10.1002/cbic.201800587 |
| Popis: | Selective and specific inhibitors of Plasmodium falciparum lysyl-tRNA synthetase represent promising therapeutic antimalarial avenues. Cladosporin was identified as a potent P. falciparum lysyl-tRNA synthetase inhibitor, with an activity against parasite lysyl-tRNA synthetase >100-fold more potent than that of the activity registered against the human enzyme. Despite its compelling activity, cladosporin exhibits poor oral bioavailability; a critical requirement for antimalarial drugs. Thus, the quest to develop metabolically stable cladosporin-derived analogues, while retaining similar selectivity and potency to that of the natural compound, has begun. Chemogenomic profiling of a designed library allowed an entirely innovative structure-activity relationship study to be initiated; this shed light on structural evidence of a privileged scaffold with a unique activity against tRNA synthetases. |
| Databáze: | OpenAIRE |
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