开发基于cetuximab抗体靶向工程酶A4H363A的ADEPT肿瘤靶向疗法

批准号:
21977055
项目类别:
面上项目
资助金额:
66.0 万元
负责人:
程剑松
依托单位:
学科分类:
生物分子的化学生物学
结题年份:
2023
批准年份:
2019
项目状态:
已结题
项目参与者:
程剑松
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中文摘要
前期,我们已经建立并验证了突变半乳糖苷酶A4H363A/6-甲基半乳糖苷前药(MeGal prodrug)的专一性激活体系(Nature Chemical Biololgy. 2019,15(2):151-160)。MeGal保护前药不被小鼠内源性酶识别,而被经过凸凹互补改造的A4H363A特异性激活。本申请将使用cetuximab抗体或其重组蛋白与改造的半乳糖苷酶A4H363A偶联(cetuximab-A4H363A)实现酶对A549(人非小细胞肺癌细胞)异源裸鼠成瘤的靶向递送。合成并筛选geldanamycin,nannocystin A(1e),nannocystin A(1e)内酰胺类似物以及10-hydroxycamptothecin (10-HCPT)的MeGal糖苷前药,联合cetuximab-A4H363A评价此抗体导向酶-前药肿瘤治疗(ADEPT)的靶向和抑瘤效果。
英文摘要
Based on the "bump-and-hole" strategy, which has been proven to be powerful for generating high-affinity protein-ligand variant pairs, we developed a novel enzyme/prodrug activation system (Nature Chemical Biololgy. 2019,15(2):151-160). First, methylation at the O-6 position of a galactosyl molecule introduced a “bump”that completely disrupts its recognition by the endogenous galactosidase (β-gal). The selectivity of an engineered β-gal (A4H363A) for the 6-methylated derivative (MeGal-drug) was achieved by introducing a“hole” at its active pocket in order to accommodate the bumpy 6-methyl group. .In this proposal, a series of prodrugs including MeGal modified geldanamycin, nannocystin A (1e), nannocystin A (1e) lactam derivative and 10-hydroxycamptothecin will be synthesized. These prodrugs will be activated by the tumor-targeted β-gal (A4H363A) coupled with cetuximab antibody for treating Non-small-cell lung carcinoma (NSCLC).
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DOI:10.1016/j.jacbts.2022.12.009
发表时间:2023-07
期刊:JACC-BASIC TO TRANSLATIONAL SCIENCE
影响因子:9.7
作者:Wei, Yongzhen;Jiang, Huan;Chai, Chao;Liu, Pei;Qian, Meng;Sun, Na;Gao, Man;Zu, Honglin;Yu, Yongquan;Ji, Guangbo;Zhang, Yating;Yang, Sen;He, Ju;Cheng, Jiansong;Tian, Jinwei;Zhao, Qiang
通讯作者:Zhao, Qiang
DOI:10.1134/s0003683821060041
发表时间:2021
期刊:APPLIED BIOCHEMISTRY AND MICROBIOLOGY
影响因子:0.8
作者:Gao M.;Fan Y.;Cheng J.
通讯作者:Cheng J.
DOI:10.1002/cjoc.202300170
发表时间:2023
期刊:Chinese Journal of Chemistry
影响因子:--
作者:Pei Liu;Xing Quan;Fangyu Wei;Xianjun Deng;Jie Shen;Jiansong Cheng
通讯作者:Jiansong Cheng
糖药物蛋白Interferonβ N-glycan的均一、人源化改造
- 批准号:81102361
- 项目类别:青年科学基金项目
- 资助金额:25.0万元
- 批准年份:2011
- 负责人:程剑松
- 依托单位:
国内基金
海外基金
