海洋放线菌来源粉蝶霉素衍生物的定向构建和以PRDX1为靶点的抗肾癌先导物优化

批准号:
81973235
项目类别:
面上项目
资助金额:
56.0 万元
负责人:
周雪峰
依托单位:
学科分类:
海洋药物
结题年份:
2023
批准年份:
2019
项目状态:
已结题
项目参与者:
周雪峰
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中文摘要
肾癌对放疗化疗均不敏感,现有药物作用靶标单一,易产生耐药性,急需研发新型抗肾癌药物。申请人前期在海洋放线菌中获得了丰富的粉蝶霉素化合物资源,发现粉蝶霉素可通过作用新靶标PRDX1,调控氧化应激并发挥抗肾癌活性。构效关系显示支链成环或糖苷化的粉蝶霉素与靶标作用更强,是先导物优化的有效策略。本项目拟对目标放线菌进行高盐胁迫和发酵优化,定向分离支链成环的新颖粉蝶霉素衍生物;构建后修饰基因缺失的突变株,产生并分离特定的粉蝶霉素糖苷;筛选糖基转移酶进行异源表达,在体外定向构建不同类型糖苷衍生物。在肾癌细胞中对衍生物进行上调PRDX1活性筛选,通过基因敲除和SPR技术验证PRDX1对衍生物的靶标作用,并建立小鼠模型进行先导物的抗肾癌评价。本项目通过理性设计和组合生物合成技术定向构建和制备粉蝶霉素衍生物,旨在发现首个以PRDX1为靶标的抗肾癌药物先导物,为我国海洋微生物来源的新型抗肾癌药物研发奠定基础。
英文摘要
Renal cancer is not sensitive to radiotherapy and chemotherapy. The targets of existing anti-renal cancer drugs are not diverse, as well as the drug resistance of renal cancer, aggravate the urgent need for the development of new renal cell carcinoma drugs. In the previous study, abundant natural piericidins were obtained in marine actinomycetes, and some of them were discovery with obvious anti-renal cancer activity, through acting on the new target PRDX1 and regulating oxidative stress in renal cancer cells. The structure-activity relationships showed that the branched chain cyclized or glycosylated piericidins had stronger action with the target, which was an effective strategy for the optimization of the lead compounds. In this project, high-salt stress and fermentation optimization will be carried out on the actinomycetes to conduct directional separation of the novel cyclized piericidin derivatives. After the construction of the special mutant strains, the new piericidin glycosides will be produced and isolated. Glycosyltransferases were screened for heterologous expression, and different glycosylated derivatives were constructed in vitro. Then, the obtained derivatives will be screened for the activity of upregulation of PRDX1 in renal cancer cells. The targeting effect of PRDX1 on derivatives was verified by SPR and gene knockout technology. At last, the mouse model will be established for the anti-renal cancer evaluation of the lead compound. Through rational design and combination of biosynthesis technology, this project aims to construct and prepare the special piericidin derivatives. By this, it’s hopeful to screen and discover the first lead compound targeting PRDX1 as anti-renal cancer agent, which lay a foundation for the development of new anti-renal cancer drugs from marine microorganisms.
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DOI:10.1177/1934578x211041420
发表时间:2021-09
期刊:Natural Product Communications
影响因子:1.8
作者:Kunlong Li;Mengdie Zhou;Ziqi Su;Xiliang Yang;Xuefeng Zhou;Jingxia Huang;Huaming Tao
通讯作者:Kunlong Li;Mengdie Zhou;Ziqi Su;Xiliang Yang;Xuefeng Zhou;Jingxia Huang;Huaming Tao
DOI:10.3390/md19080428
发表时间:2021-07-28
期刊:Marine drugs
影响因子:5.4
作者:Li K;Su Z;Gao Y;Lin X;Pang X;Yang B;Tao H;Luo X;Liu Y;Zhou X
通讯作者:Zhou X
DOI:10.3390/md20040259
发表时间:2022-04-07
期刊:Marine drugs
影响因子:5.4
作者:
通讯作者:
DOI:10.3389/fchem.2019.00879
发表时间:2020
期刊:Frontiers in Chemistry
影响因子:5.5
作者:Li Kunlong;Cai Jian;Su Ziqi;Yang Bin;Liu Yonghong;Zhou Xuefeng;Huang Jingxia;Tao Huaming
通讯作者:Tao Huaming
DOI:10.1021/acs.jmedchem.1c00175
发表时间:2021-07-12
期刊:JOURNAL OF MEDICINAL CHEMISTRY
影响因子:7.3
作者:Liang, Zhi;Chen, Yulian;Tang, Lan
通讯作者:Tang, Lan
红树林底泥微生物中抗纤维化药源分子的定向挖掘和机制研究
- 批准号:--
- 项目类别:省市级项目
- 资助金额:15.0万元
- 批准年份:2024
- 负责人:周雪峰
- 依托单位:
南海深海放线菌中gp41为靶点的HIV进入抑制剂的筛选发现
- 批准号:41376162
- 项目类别:面上项目
- 资助金额:78.0万元
- 批准年份:2013
- 负责人:周雪峰
- 依托单位:
基于海绵化学防御功能的抗菌活性成分研究
- 批准号:20902094
- 项目类别:青年科学基金项目
- 资助金额:19.0万元
- 批准年份:2009
- 负责人:周雪峰
- 依托单位:
国内基金
海外基金
