Reprogramming of Protein-Targeted Small-Molecule Medicines to RNA by Ribonuclease Recruitment.
Reprogramming of Protein-Targeted Small-Molecule Medicines to RNA by Ribonuclease Recruitment.
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DOI：
10.1021/jacs.1c02248
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发表时间：
2021-08-25
影响因子：
15
通讯作者：
Disney, Matthew D.
中科院分区：
文献类型：
--
作者：
Zhang, Peiyuan;Liu, Xiaohui;Abegg, Daniel;Tanaka, Toru;Tong, Yuquan;Benhamou, Raphael I.;Baisden, Jared;Crynen, Gogce;Meyer, Samantha M.;Cameron, Michael D.;Chatterjee, Arnab K.;Adibekian, Alexander;Childs-Disney, Jessica L.;Disney, Matthew D.
将已知药物重新编程为具有活性和选择性的新靶点是具有挑战性的。通过研究RNA折叠和已知小分子药物之间的结合相互作用，并挖掘人类RNA之间的所得数据集，我们确定了Dovitinib，一种受体酪氨酸激酶（RTK）抑制剂，结合microRNA-21（pre-miR-21）的前体。Dovitinib通过将其用作嵌合化合物中的RNA识别元件而被合理地重编程为pre-miR-21，所述嵌合化合物还募集RNA酶L以诱导RNA的催化降解。通过增强固有的RNA靶向活性和降低对细胞中典型RTK蛋白靶点的效力，嵌合体将对pre-miR-21的选择性改变了2500倍，减轻了三阴性乳腺癌和Alport综合征小鼠模型中的疾病进展，这两种疾病都是由miR-21过表达引起的。因此，靶向降解可以显著提高甚至跨不同生物分子的选择性，即，蛋白质与RNA的对比
Reprogramming known medicines for a novel target with activity and selectivity over the canonical target is challenging. By studying the binding interactions between RNA folds and known small-molecule medicines and mining the resultant dataset across human RNAs, we identified that Dovitinib, a receptor tyrosine kinase (RTK) inhibitor, binds the precursor to microRNA-21 (pre-miR-21). Dovitinib was rationally reprogrammed for pre-miR-21 by using it as an RNA recognition element in a chimeric compound that also recruits RNase L to induce the RNA’s catalytic degradation. By enhancing the inherent RNA-targeting activity and decreasing potency against canonical RTK protein targets in cells, the chimera shifted selectivity for pre-miR-21 by 2500-fold, alleviating disease progression in mouse models of triple-negative breast cancer and Alport Syndrome, both caused by miR-21 overexpression. Thus, targeted degradation can dramatically improve selectivity even across different biomolecules, i.e., protein versus RNA.
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DOI：
10.1073/pnas.1810137115
发表时间：
2018-10-16
影响因子：
11.1
作者：
Janes J;Young ME;Chen E;Rogers NH;Burgstaller-Muehlbacher S;Hughes LD;Love MS;Hull MV;Kuhen KL;Woods AK;Joseph SB;Petrassi HM;McNamara CW;Tremblay MS;Su AI;Schultz PG;Chatterjee AK
通讯作者：
Chatterjee AK
影响因子：
3
作者：
Liu B;Childs-Disney JL;Znosko BM;Wang D;Fallahi M;Gallo SM;Disney MD
通讯作者：
Disney MD
DOI：
10.1016/j.omtn.2018.09.004
发表时间：
2018-12-07
期刊：
Molecular therapy. Nucleic acids
影响因子：
--
作者：
Ding T;Cui P;Zhou Y;Chen C;Zhao J;Wang H;Guo M;He Z;Xu L
通讯作者：
Xu L
影响因子：
2.7
作者：
Sakamoto, Kotaro;Otake, Kentaro;Umemoto, Tadashi
通讯作者：
Umemoto, Tadashi
影响因子：
64.8
作者：
Riva L;Yuan S;Yin X;Martin-Sancho L;Matsunaga N;Pache L;Burgstaller-Muehlbacher S;De Jesus PD;Teriete P;Hull MV;Chang MW;Chan JF;Cao J;Poon VK;Herbert KM;Cheng K;Nguyen TH;Rubanov A;Pu Y;Nguyen C;Choi A;Rathnasinghe R;Schotsaert M;Miorin L;Dejosez M;Zwaka TP;Sit KY;Martinez-Sobrido L;Liu WC;White KM;Chapman ME;Lendy EK;Glynne RJ;Albrecht R;Ruppin E;Mesecar AD;Johnson JR;Benner C;Sun R;Schultz PG;Su AI;García-Sastre A;Chatterjee AK;Yuen KY;Chanda SK
通讯作者：
Chanda SK