NIBR-Novartis Institute for Biomedical Research, Fabrikstrasse 22-1.051.17, 4054, Basel, Switzerland.
Department of Chemistry, Imperial College, London, SW7 2AZ, UK.
Chembiochem. 2019 Mar 1;20(5):644-649. doi: 10.1002/cbic.201800587. Epub 2019 Feb 4.
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.
疟原虫赖氨酸 tRNA 合成酶的选择性和特异性抑制剂是很有前途的抗疟治疗方法。克拉多菌素被鉴定为一种有效的疟原虫赖氨酸 tRNA 合成酶抑制剂，对寄生虫赖氨酸 tRNA 合成酶的活性比其对人酶的活性强 100 多倍。尽管克拉多菌素具有很强的活性，但它的口服生物利用度很差；这是抗疟药物的一个关键要求。因此，人们开始寻求开发代谢稳定的克拉多菌素衍生类似物，同时保持与天然化合物相似的选择性和效力。设计文库的化学生物基因组学分析允许启动一项全新的结构-活性关系研究；这揭示了对独特的 tRNA 合成酶有独特活性的特权支架的结构证据。
