Chemical Conjugation of Evans Blue Derivative: A Strategy to Develop Long-Acting Therapeutics through Albumin Binding.
Chemical Conjugation of Evans Blue Derivative: A Strategy to Develop Long-Acting Therapeutics through Albumin Binding.
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作者：
Chen H;Wang G;Lang L;Jacobson O;Kiesewetter DO;Liu Y;Ma Y;Zhang X;Wu H;Zhu L;Niu G;Chen X
治疗药物的疗效在很大程度上取决于其在体内的最佳药代动力学。白蛋白偶联被认为是延长肽类和蛋白质短半衰期的最有效方法之一。在这项研究中，我们提出了一个新的平台，通过将一种小分子白蛋白结合部分——截短的伊文思蓝，与肽类或蛋白质偶联来开发长效治疗药物。以抗糖尿病肽类药物艾塞那肽 - 4作为模型肽，我们合成了一种新的长效艾塞那肽 - 4衍生物（称为Abextide）。通过与白蛋白原位络合，Abextide的生物半衰期显著延长。与艾塞那肽 - 4相比，Abextide的降糖效果也显著提高。因此，Abextide在治疗2型糖尿病方面具有相当大的潜力。这种策略作为一个通用的技术平台，可应用于其他小分子和生物制品，用于开发长效治疗药物。
The efficacy of therapeutic drugs is highly dependent on their optimal in vivo pharmacokinetics. Albumin conjugation is considered to be one of the most effective means of protracting the short lifespan of peptides and proteins. In this study, we proposed a novel platform for developing long lasting therapeutics by conjugating a small molecular albumin binding moiety, truncated Evans blue, to either peptides or proteins. Using the anti-diabetic peptide drug Exendin-4 as a model peptide, we synthesized a new long-acting Exendin-4 derivative (denoted as Abextide). Through complexation with albumin in situ, the biological half-life of Abextide was significantly extended. The hypoglycemic effect of Abextide was also improved remarkably over Exendin-4. Thus, Abextide has considerable potential to treat type 2 diabetes. This strategy as a general technology platform can be applied to other small molecules and biologics for the development of long-acting therapeutic drugs.