Synthesis and evaluation of a deltic guanidinium analogue of a cyclic RGD peptide
Synthesis and evaluation of a deltic guanidinium analogue of a cyclic RGD peptide
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DOI：
10.1039/d3ob00089c
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发表时间：
2023-02-01
影响因子：
3.2
通讯作者：
Ogawa, Kazuma
中科院分区：
文献类型：
--
作者：
Mishiro, Kenji;Ueno, Takahiro;Ogawa, Kazuma
胍基在天然产物和药物中大量存在。在自然界中许多常见的官能团中，胍的碱性最高。由于其高碱性，它通常以质子化胍存在，并作为阳离子氢键供体。由于胍盐的高碱度和独特的三角平面形状，寻找适当的生物电子等排体是具有挑战性的。在这项研究中，我们探讨了“deltic guanidinium”作为生物电子等排体的胍使用环甘氨酸-甘氨酸-天冬氨酸（RGD）肽作为母体化合物的可能性。我们合成了c（deltic RGDyK），其中c（RGDyK）中精氨酸残基的胍基被deltic guanidinium取代。使用c（deltic RGDyK）及其放射性碘标记变体进行了靶向结合试验、生物分布研究和代谢稳定性试验。Deltic胍类似物肽表现出与母体肽相似的生物学性质，并且改善了体内稳定性，表明Deltic胍可以作为胍的独特生物电子等排体。
A guanidine group is abundantly found in natural products and drugs. Guanidine has the highest basicity among many common functional groups in nature. Because of its high basicity, it generally exists as a protonated guanidinium and functions as a cationic hydrogen bond donor. Finding an appropriate bioisostere of guanidinium is challenging because of its high basicity and unique trigonal planar shape. In this study, we explored the possibility of "deltic guanidinium" as a bioisostere of guanidinium using a cyclic arginine-glycine-aspartic acid (RGD) peptide as a parent compound. We synthesized c(deltic RGDyK), in which a guanidinium group of an arginine residue in c(RGDyK) is replaced with deltic guanidinium. A target binding assay, biodistribution study, and metabolic stability assay were conducted with c(deltic RGDyK) and its radioiodinated variant. The deltic guanidinium analog peptides exhibited similar biological properties to the parent peptides and improved in vivo stability, indicating that deltic guanidinium could work as a unique bioisostere of guanidinium.