Inhibition of Plasmodium falciparum Lysyl-tRNA synthetase via an anaplastic lymphoma kinase inhibitor.
Inhibition of Plasmodium falciparum Lysyl-tRNA synthetase via an anaplastic lymphoma kinase inhibitor.
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通过间变性淋巴瘤激酶抑制剂抑制恶性疟原虫赖氨酰-tRNA 合成酶。
DOI：
10.1093/nar/gkaa862
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发表时间：
2020-11-18
影响因子：
14.9
通讯作者：
Fang P
中科院分区：
文献类型：
--
作者：
Zhou J;Huang Z;Zheng L;Hei Z;Wang Z;Yu B;Jiang L;Wang J;Fang P
氨酰-tRNA合成酶是开发抗细菌、抗真菌、抗寄生虫剂和治疗其他人类疾病的有吸引力的靶标。来自该家族的赖氨酰-tRNA合成酶（LysRS）已被验证为开发抗疟疾药物的有希望的靶点。在这里，我们开发了一个高通量的兼容检测和筛选1215生物活性化合物，以确定恶性疟原虫胞质LysRS（PfLysRS）抑制剂。ASP 3026是一种间变性淋巴瘤激酶抑制剂，在临床试验中用于治疗B细胞淋巴瘤和实体瘤，被确定为一种新型PfLysRS抑制剂。ASP 3026在纳摩尔效力下抑制PfLysRS的酶活性，其有效性比抑制人对应物高>380倍。此外，该化合物抑制血液阶段的恶性疟原虫生长。为了了解ASP 3026抑制的分子机制，我们进一步解析了PfLysRS-ASP 3026的共晶结构，分辨率为2.49 nm，为进一步优化化合物提供了线索。最后，一级构效关系分析表明，ASP 3026对PfLysRS的抑制作用具有高度的结构特异性。这项工作不仅为抗疟药物的开发提供了一种新的具有良好可药性的化学支架，而且还突出了将激酶抑制药物重新利用为tRNA合成酶抑制剂来治疗人类疾病的潜力。
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 (PfLysRS) 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 PfLysRS inhibitor. ASP3026 suppresses the enzymatic activity of PfLysRS 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 PfLysRS-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 PfLysRS 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.
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影响因子：
4.4
作者：
Bhatt TK;Kapil C;Khan S;Jairajpuri MA;Sharma V;Santoni D;Silvestrini F;Pizzi E;Sharma A
通讯作者：
Sharma A
影响因子：
7.3
作者：
Das, Pronay;Babbar, Palak;Reddy, D. Srinivasa
通讯作者：
Reddy, D. Srinivasa
化学抑制前抗赖氨酸-TRNA合成酶 - 氯胺酮受体相互作用的化学抑制作用。
影响因子：
14.8
作者：
Kim, Dae Gyu;Lee, Jin Young;Kwon, Nam Hoon;Fang, Pengfei;Zhang, Qian;Wang, Jing;Young, Nicolas L.;Guo, Min;Cho, Hye Young;Mushtaq, Ameeq Ul;Jeon, Young Ho;Choi, Jin Woo;Han, Jung Min;Kang, Ho Woong;Joo, Jae Eun;Hur, Youn;Kang, Wonyoung;Yang, Heekyoung;Nam, Do-Hyun;Lee, Mi-Sook;Lee, Jung Weon;Kim, Eun-Sook;Moon, Aree;Kim, Kibom;Kim, Doyeun;Kang, Eun Joo;Moon, Youngji;Rhee, Kyung Hee;Han, Byung Woo;Yang, Jee Sun;Han, Gyoonhee;Yang, Won Suk;Lee, Cheolju;Wang, Ming-Wei;Kim, Sunghoon
通讯作者：
Kim, Sunghoon
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
DOI：
10.1177/0954411912474611
发表时间：
2013-01-01
影响因子：
1.8
作者：
Karimi, Alireza;Navidbakhsh, Mahdi;Faghihi, Shahab
通讯作者：
Faghihi, Shahab