胸腺素α1类似物的定点PEG修饰及其免疫活性评价

PEG修饰是改善蛋白质及肽类药物药代动力学特性的有效途径。然而与蛋白质相比，肽类化合物的分子较小，PEG的分子体积较大，其长链很可能会遮蔽肽的活性位点。因此，肽类化合物PEG修饰的位置和数量对于保持肽的生物活性至关重要。为阐明PEG修饰的位置与肽生物活性之间的关系，对肽类药物日达仙（胸腺素α1，Tα1）进行了定点修饰。Tα1具有α-螺旋、β-转角和无规卷曲的结构区域。分别在这些区域选择不同的位点进行PEG修饰。PEG的定点修饰是通过引入Cys，利用其-SH与mPEG-MAL的特异性反应而实现的。Con A刺激下的脾细胞产生IFN-γ试验的初步结果表明，PEG修饰对活性的影响与修饰的位置有一定的关系，大多数情况下，PEG修饰能保持Tα1的免疫活性。PEG修饰的位点对于保持肽的生物活性是很重要的。

Site‐directed PEGylations of Thymosin α 1 Analogs and Evaluation of Their Immunoactivity

PEGylation is an effective way to improve the pharmacokinetic profiles of pharmaceutical proteins or peptides. But the relatively large and long PEG chains would be likely to shelter the active site of a small peptide because of its small size, compared with a protein. Therefore, the positions and numbers of PEGylation are crucial for the bioactivity of a PEGylated peptide. To elucidate the relationship between the PEGylated positions and bioactivity of a peptide drug, site‐specific PEGylations were performed on Zadaxin (Thymosin α 1, Tα1), which is a pharmaceutical peptide with an α‐helix region, a β‐turn region, and random coils. Site‐specific mono‐PEGylations of Tα1 in different conformational regions were realized through introducing one cysteine residue into the desired positions of the peptide, followed by a coupling reaction with a thiol‐attached maleimide‐PEG reagent. Primary data from IFN‐γ production of splenocytes induced by Con A showed that the influence of PEGylation on Zadaxin was position‐dependent, and mostly, positive effects were observed after PEGylation, which indicated that the position of PEGylation is important for maintaining the bioactivity of a peptide.