Impact of the Proline Residue on Ligand Binding of Neurotensin Receptor 2 (NTS2)-Selective Peptide-Peptoid Hybrids
Impact of the Proline Residue on Ligand Binding of Neurotensin Receptor 2 (NTS2)-Selective Peptide-Peptoid Hybrids
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DOI：
10.1002/cmdc.201300054
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发表时间：
2013-05-01
期刊：
影响因子：
3.4
通讯作者：
Gmeiner, Peter
中科院分区：
文献类型：
--
作者：
Held, Cornelia;Huebner, Harald;Gmeiner, Peter
为了研究选择性神经降压素受体2（NTS 2）配体的结合模式和结构反应性关系（SAR），开发了模拟内源性配体功能的新型肽类肽杂合体。从我们最近描述的1型NTSC 2配体开始，开发了2型的结构变体和代谢稳定的类似物3a、B。用一系列结构替代物替换脯氨酸单元，并对NTS 2亲和力和选择性的相应分子探针进行评价，结果表明与结合亚型NTS 1的NT（813）衍生物相似的SAR。肽类杂合体2d、3a、B显示出实质性的NTS 2结合亲和力（Ki= 8.116 nM）和超过NTS 1的24008600倍的选择性。噻唑烷衍生物3b在血清降解试验中显示出超过32小时的代谢稳定性。在磷酸肌醇积累试验中，神经降压素模拟物3a和3b显示出超过NT（813）活性的1.7 - 2.0倍的组成性活性抑制。氟化衍生物3a可以通过19 F磁共振成像提供有吸引力的机会来检测NTS 2。
To investigate the binding mode and structureactivity relationships (SARs) of selective neurotensin receptor2 (NTS2) ligands, novel peptidepeptoid hybrids that simulate the function of the endogenous ligand were developed. Starting from our recently described NTS2 ligands of type 1, structural variants of type 2 and the metabolically stable analogues 3a,b were developed. Replacement of the proline unit by a collection of structural surrogates and evaluation of the respective molecular probes for NTS2 affinity and selectivity indicated similar SARs as described for NT(813) derivatives bound to the subtype NTS1. Peptidepeptoid hybrids 2d, 3a,b showed substantial NTS2 binding affinity (Ki=8.116nM) and 24008600-fold selectivity over NTS1. The thiazolidine derivative 3b showed metabolic stability over 32h in a serum degradation assay. In an inositol phosphate accumulation assay, the neurotensin mimetics 3a and 3b displayed an inhibition of constitutive activity exceeding 1.72.0times the activity of NT(813). The fluorinated derivative 3a could afford attractive opportunities to detect NTS2 by 19F magnetic resonance imaging.