Multivalent antiviral XTEN-peptide conjugates with long in vivo half-life and enhanced solubility.
Multivalent antiviral XTEN-peptide conjugates with long in vivo half-life and enhanced solubility.
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DOI：
10.1021/bc500215m
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发表时间：
2014-07-16
影响因子：
4.7
通讯作者：
Schellenberger, Volker
中科院分区：
文献类型：
--
作者：
Ding, Sheng;Song, Michael;Sim, Bee-Cheng;Gu, Chen;Podust, Vladimir N.;Wang, Chia-Wei;McLaughlin, Bryant;Shah, Trishul P.;Lax, Rodney;Gast, Rainer;Sharan, Rahul;Vasek, Arthur;Hartman, M. Amanda;Deniston, Colin;Srinivas, Prathna;Schellenberger, Volker
XTEN是一种非结构化、非重复性蛋白质聚合物，旨在通过引入类似于聚乙二醇的膨胀效应来延长药物的体内半衰期。虽然XTEN可以表达为具有生物活性蛋白和肽的重组融合蛋白，但感兴趣的治疗分子也可以化学缀合至XTEN。这种方法允许精确控制生物活性部分沿着XTEN长度的定位、间隔和化合价。我们已经证明了T-20（一种用于治疗HIV-1多药耐药患者的抗逆转录病毒肽）与XTEN的连接。通过使马来酰亚胺官能化的T-20与含半胱氨酸的XTEN反应并改变XTEN中半胱氨酸的数量和位置，产生了不同肽-聚合物组合的文库。使用体外抗病毒试验对T-20-XTEN缀合物进行了测试，发现其可有效抑制HIV-1进入并防止细胞死亡，其中T-20肽的拷贝数和间距影响抗病毒活性。还发现肽-XTEN缀合物与天然T-20肽相比具有增强的溶解度。在大鼠中测定了最具活性的T-20-XTEN结合物的药代动力学特征，发现其消除半衰期为55.7 ± 17.7 h，几乎是大鼠中报告的T-20给药半衰期的20倍。由于T-20与XTEN的缀合极大地改善了肽的体内半衰期和溶解度，因此XTEN平台已被证明是用于改善药物性质并能够开发一类下一代治疗剂的通用工具。
XTENs are unstructured, nonrepetitive protein polymers designed to prolong the in vivo half-life of pharmaceuticals by introducing a bulking effect similar to that of poly(ethylene glycol). While XTEN can be expressed as a recombinant fusion protein with bioactive proteins and peptides, therapeutic molecules of interest can also be chemically conjugated to XTEN. Such an approach permits precise control over the positioning, spacing, and valency of bioactive moieties along the length of XTEN. We have demonstrated the attachment of T-20, an anti-retroviral peptide indicated for the treatment of HIV-1 patients with multidrug resistance, to XTEN. By reacting maleimide-functionalized T-20 with cysteine-containing XTENs and varying the number and positioning of cysteines in the XTENs, a library of different peptide–polymer combinations were produced. The T-20-XTEN conjugates were tested using an in vitro antiviral assay and were found to be effective in inhibiting HIV-1 entry and preventing cell death, with the copy number and spacing of the T-20 peptides influencing antiviral activity. The peptide–XTEN conjugates were also discovered to have enhanced solubilities in comparison with the native T-20 peptide. The pharmacokinetic profile of the most active T-20-XTEN conjugate was measured in rats, and it was found to exhibit an elimination half-life of 55.7 ± 17.7 h, almost 20 times longer than the reported half-life for T-20 dosed in rats. As the conjugation of T-20 to XTEN greatly improved the in vivo half-life and solubility of the peptide, the XTEN platform has been demonstrated to be a versatile tool for improving the properties of drugs and enabling the development of a class of next-generation therapeutics.
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影响因子：
5.8
作者：
Yuen, Kevin C. J.;Conway, Gerard S.;Cleland, Jeffrey L.
通讯作者：
Cleland, Jeffrey L.
影响因子：
3.7
作者：
Chang CH;Hinkula J;Loo M;Falkeborn T;Li R;Cardillo TM;Rossi EA;Goldenberg DM;Wahren B
通讯作者：
Wahren B
影响因子：
2.4
作者：
Podust, Vladimir N.;Sim, Bee-Cheng;Schellenberger, Volker
通讯作者：
Schellenberger, Volker
影响因子：
4.8
作者：
He, Yuxian;Xiao, Yonghong;Zhang, Linqi
通讯作者：
Zhang, Linqi
影响因子：
158.5
作者：
Lalezari, JP;Henry, K;Hersch, J
通讯作者：
Hersch, J