Premium
Design and Synthesis of Metabolically Stable tRNA Synthetase Inhibitors Derived from Cladosporin
Author(s) -
Rusch Marion,
Theve Arnaud,
Hoepfner Dominic,
Aust Thomas,
Studer Christian,
Patoor Maude,
Rollin Patrick,
Livendahl Madeleine,
Ranieri Beatrice,
Schmitt Esther,
Spanka Carsten,
Gademann Karl,
Bouchez Laure C.
Publication year - 2019
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201800587
Subject(s) - biochemistry , plasmodium falciparum , enzyme , aminoacyl trna synthetase , biology , transfer rna , chemistry , gene , rna , malaria , immunology
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.