Thrombin rapidly digests adrenomedullin: Synthesis of adrenomedullin analogs resistant to thrombin
Thrombin rapidly digests adrenomedullin: Synthesis of adrenomedullin analogs resistant to thrombin
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DOI：
10.1016/j.bbrc.2020.06.057
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发表时间：
2020-08-27
影响因子：
3.1
通讯作者：
Kitamura, Kazuo
中科院分区：
文献类型：
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作者：
Nishimoto, Yayoi;Nagata, Sayaka;Kitamura, Kazuo
人肾上腺髓质素（AM）是一种具有多种生物学活性的循环激素和局部旁分泌介质。我们研究了AM的代谢，通过检查其在人血清中的碎片。肾上腺髓质素在人血清中迅速裂解，但在血浆中相对稳定。结果表明，凝血酶能迅速消化血清中的AM，主要产物为AM（13-44）。在这些数据的基础上，我们制备了其中Arg-44分别被Ala、Lys和D-Arg取代的AM类似物。这些类似物对凝血酶具有抗性，并显示出与天然AM相当的生物活性。此外，这些肽在大鼠皮下给药后的生物利用度提高。这些AM类似物可能是有希望的临床应用的候选药物。(C)2020由Elsevier Inc.出版。
Human adrenomedullin (AM) functions as a circulating hormone and as a local paracrine mediator with multiple biological activities. We investigated the metabolism of AM by examining its fragmentation in human serum. Adrenomedullin was rapidly cleaved in human serum, but was relatively stable in plasma. We showed that AM was rapidly digested by thrombin in serum, with AM(13-44) as the main product. On the basis of these data, we prepared AM analogs in which Arg-44 was replaced by Ala, Lys, and D-Arg, respectively. These analogs were resistant to thrombin and showed comparable biological activity to native AM. Furthermore, the bioavailabilities of these peptides were improved after subcutaneous administration in rats. These AM analogs may be promising drug candidates for clinical applications. (C) 2020 Published by Elsevier Inc.