A better anti-diabetic recombinant human fibroblast growth factor 21 (rhFGF21) modified with polyethylene glycol.
A better anti-diabetic recombinant human fibroblast growth factor 21 (rhFGF21) modified with polyethylene glycol.
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聚乙二醇修饰的更好的抗糖尿病重组人成纤维细胞生长因子 21 (rhFGF21)
DOI：
10.1371/journal.pone.0020669
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Huang Z;Wang H;Lu M;Sun C;Wu X;Tan Y;Ye C;Zhu G;Wang X;Cai L;Li X
FGF 21作为成纤维细胞生长因子（FGF）家族成员之一，作为抗代谢性疾病的候选药物已被广泛研究。在本研究中，用聚乙二醇（PEG化）修饰重组人FGF 21（rhFGF 21），以提高其体内生物稳定性和治疗效力。在N-末端残基处，用mPEG 20 kDa-丁醛对rhFGF 21进行位点选择性PEG化。通过Q Sepharose阴离子交换层析将PEG化的rhFGF 21纯化至接近均一。在2型糖尿病大鼠模型中评价PEG化rhFGF 21的一般结构和生化特征以及抗糖尿病作用。通过N-末端测序和MALDI-TOF质谱分析，我们证实PEG分子仅与rhFGF 21的N-末端结合。单聚乙二醇修饰的rhFGF 21保留了天然rhFGF 21的二级结构，但其生物稳定性，包括对生理温度和胰蛋白酶消化的耐受性，显著增强。PEG化rhFGF 21的体内免疫原性显著降低，体内半衰期显著延长。与天然形式相比，PEG化的rhFGF 21在体外具有类似的刺激3 T3-L1细胞中葡萄糖摄取的能力，但在2型糖尿病动物中提供了显著的降低血糖和甘油三酯水平的长期效果。这些结果表明，PEG化的rhFGF 21是比目前可用的天然rhFGF 21更好和更有效的抗糖尿病候选药物。因此，聚乙二醇修饰的rhFGF 21有望应用于临床改善2型糖尿病患者的代谢综合征。
As one of fibroblast growth factor (FGF) family members, FGF21 has been extensively investigated for its potential as a drug candidate to combat metabolic diseases. In the present study, recombinant human FGF21 (rhFGF21) was modified with polyethylene glycol (PEGylation) in order to increase its in vivo biostabilities and therapeutic potency. At N-terminal residue rhFGF21 was site-selectively PEGylated with mPEG20 kDa-butyraldehyde. The PEGylated rhFGF21 was purified to near homogeneity by Q Sepharose anion-exchange chromatography. The general structural and biochemical features as well as anti-diabetic effects of PEGylated rhFGF21 in a type 2 diabetic rat model were evaluated. By N-terminal sequencing and MALDI-TOF mass spectrometry, we confirmed that PEG molecule was conjugated only to the N-terminus of rhFGF21. The mono-PEGylated rhFGF21 retained the secondary structure, consistent with the native rhFGF21, but its biostabilities, including the resistance to physiological temperature and trypsinization, were significantly enhanced. The in vivo immunogenicity of PEGylated rhFGF21 was significantly decreased, and in vivo half-life time was significantly elongated. Compared to the native form, the PEGylated rhFGF21 had a similar capacity of stimulating glucose uptake in 3T3-L1 cells in vitro, but afforded a significantly long effect on reducing blood glucose and triglyceride levels in the type 2 diabetic animals. These results suggest that the PEGylated rhFGF21 is a better and more effective anti-diabetic drug candidate than the native rhFGF21 currently available. Therefore, the PEGylated rhFGF21 may be potentially applied in clinics to improve the metabolic syndrome for type 2 diabetic patients.
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DOI：
10.1073/pnas.0701600104
发表时间：
2007-05-01
影响因子：
11.1
作者：
Ogawa, Yasushi;Kurosu, Hiroshi;Kuro-o, Makoto
通讯作者：
Kuro-o, Makoto
影响因子：
2.9
作者：
KURFURST, MM
通讯作者：
KURFURST, MM
DOI：
10.1016/0006-291x(90)90839-f
发表时间：
1990-09-28
影响因子：
3.1
作者：
KITAMURA, K;TAKAHASHI, T;HAKOMORI, S
通讯作者：
HAKOMORI, S
影响因子：
3.5
作者：
Izumiya, Yasuhiro;Bina, Holly A.;Ouchi, Noriyuki;Akasaki, Yuichi;Kharitonenkov, Alexei;Walsh, Kenneth
通讯作者：
Walsh, Kenneth
影响因子：
5.6
作者：
Micanovic, Radmila;Raches, David W.;Kharitonenkov, Alexei
通讯作者：
Kharitonenkov, Alexei