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Structure-guided conversion from an anaplastic lymphoma kinase inhibitor into Plasmodium lysyl-tRNA synthetase selective inhibitors.

Authors :
Zhou, Jintong
Xia, Mingyu
Huang, Zhenghui
Qiao, Hang
Yang, Guang
Qian, Yunan
Li, Peifeng
Zhang, Zhaolun
Gao, Xinai
Jiang, Lubin
Wang, Jing
Li, Wei
Fang, Pengfei
Source :
Communications Biology; 6/18/2024, Vol. 7 Issue 1, p1-11, 11p
Publication Year :
2024

Abstract

Aminoacyl-tRNA synthetases (aaRSs) play a central role in the translation of genetic code, serving as attractive drug targets. Within this family, the lysyl-tRNA synthetase (LysRS) constitutes a promising antimalarial target. ASP3026, an anaplastic lymphoma kinase (ALK) inhibitor was recently identified as a novel Plasmodium falciparum LysRS (PfLysRS) inhibitor. Here, based on cocrystal structures and biochemical experiments, we developed a series of ASP3026 analogues to improve the selectivity and potency of LysRS inhibition. The leading compound 36 showed a dissociation constant of 15.9 nM with PfLysRS. The inhibitory efficacy on PfLysRS and parasites has been enhanced. Covalent attachment of l-lysine to compound 36 resulted in compound 36K3, which exhibited further increased inhibitory activity against PfLysRS but significantly decreased activity against ALK. However, its inhibitory activity against parasites did not improve, suggesting potential future optimization directions. This study presents a new example of derivatization of kinase inhibitors repurposed to inhibit aaRS. Using a combination of biochemical and structural approaches, the authors demonstrate that derivatization of kinase inhibitors can yield new repurposed anti-malarial drugs that specifically target Plasmodium falciparum Lysine-tRNA synthetase. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
23993642
Volume :
7
Issue :
1
Database :
Complementary Index
Journal :
Communications Biology
Publication Type :
Academic Journal
Accession number :
177963382
Full Text :
https://doi.org/10.1038/s42003-024-06455-4