Inhibition of Plasmodium falciparum Lysyl-tRNA synthetase via an anaplastic lymphoma kinase inhibitor. Issue 20 (14th October 2020)

• Record Type: Journal Article
• Authors: Zhou, Jintong; Huang, Zhenghui; Zheng, Li; Hei, Zhoufei; Wang, Zhiyong; Yu, Biao; Jiang, Lubin; Wang, Jing; Fang, Pengfei
• Is Part Of: Nucleic acids research. Volume 48:Issue 20(2020)
• Page Start: 11566
• Page End: 11576
• Publication Date: 2020-10-14
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkaa862
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: Aminoacyl-tRNA synthetases are attractive targets for the development of antibacterial, antifungal, antiparasitic agents and for the treatment of other human diseases. Lysyl-tRNA synthetase (LysRS) from this family has been validated as a promising target for the development of antimalarial drugs. Here, we developed a high-throughput compatible assay and screened 1215 bioactive compounds to identify Plasmodium falciparum cytoplasmic LysRS ( Pf LysRS) inhibitor. ASP3026, an anaplastic lymphoma kinase inhibitor that was used in clinical trials for the treatment of B-cell lymphoma and solid tumors, was identified as a novel Pf LysRS inhibitor. ASP3026 suppresses the enzymatic activity of Pf LysRS at nanomolar potency, which is >380-fold more effective than inhibition of the human counterpart. In addition, the compound suppressed blood-stage P. falciparum growth. To understand the molecular mechanism of inhibition by ASP3026, we further solved the cocrystal structure of Pf LysRS-ASP3026 at a resolution of 2.49 Å, providing clues for further optimization of the compound. Finally, primary structure-activity relationship analyses indicated that the inhibition of Pf LysRS by ASP3026 is highly structure specific. This work not only provides a new chemical scaffold with good druggability for antimalarial development but also highlights the potential for repurposing kinase-inhibiting drugs to tRNA synthetase inhibitors to treat human diseases.