| Affiliation: | 1. NIBR–Novartis Institute for Biomedical Research, Fabrikstrasse 22-1.051.17, 4054 Basel, Switzerland;2. NIBR–Novartis Institute for Biomedical Research, Fabrikstrasse 22-1.051.17, 4054 Basel, Switzerland Department of Chemistry, Imperial College, London, SW7 2AZ UK;3. Institut de Chimie Organique et Analytique (ICOA), UMR7311, Université d'Orléans, 45100 Orléans, France;4. University of Zürich, Department of Chemistry, Winterthurerstrasse 190, 8057 Zürich, Switzerland |
| Abstract: | 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. |
