A biomimetic approach for enhancing the in vivo half-life of peptides.
A biomimetic approach for enhancing the in vivo half-life of peptides.
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DOI：
10.1038/nchembio.1907
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发表时间：
2015-10
影响因子：
14.8
通讯作者：
Alhamadsheh MM
中科院分区：
文献类型：
--
作者：
Penchala SC;Miller MR;Pal A;Dong J;Madadi NR;Xie J;Joo H;Tsai J;Batoon P;Samoshin V;Franz A;Cox T;Miles J;Chan WK;Park MS;Alhamadsheh MM
肽的巨大治疗潜力尚未实现，主要是由于其短的体内半衰期。虽然与大分子缀合已经是提高蛋白质半衰期的主要方法，但大分子的空间位阻通常损害肽与靶受体的结合，从而损害体内功效。在这里，我们报告了一种新的策略，提高在体内半衰期的肽，而不损害其效力。我们的方法包括赋予肽一个小分子，可逆地结合到血清蛋白，甲状腺素运载蛋白。虽然有几个可逆的白蛋白结合分子，我们不知道设计的小分子，可逆地结合到其他血清蛋白，并用于在体内延长半衰期。我们在这里表明，我们的策略确实有效地提高了GnRH受体激动剂的半衰期，同时保持其结合亲和力，这被转化为上级体内疗效。
The tremendous therapeutic potential of peptides has not yet been realized, mainly due to their short in vivo half-life. While conjugation to macromolecules has been a mainstay approach for enhancing the half-life of proteins, the steric hindrance of macromolecules often harms the binding of peptides to target receptors, compromising the in vivo efficacy. Here we report a new strategy for enhancing the in vivo half-life of peptides without compromising their potency. Our approach involves endowing peptides with a small-molecule that binds reversibly to the serum protein, transthyretin. Although there are few reversible albumin-binding molecules, we are unaware of designed small molecules that bind reversibly to other serum proteins and are used for half-life extension in vivo. We show here that our strategy was indeed effective in enhancing the half-life of an agonist for GnRH receptor while maintaining its binding affinity, which was translated into superior in vivo efficacy.