Design and characterization of α-melanotropin peptide analogs cyclized through rhenium and technetium metal coordination
Design and characterization of α-melanotropin peptide analogs cyclized through rhenium and technetium metal coordination
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DOI：
10.1073/pnas.95.22.12814
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发表时间：
1998-10-27
影响因子：
11.1
通讯作者：
Quinn, TP
中科院分区：
文献类型：
--
作者：
Giblin, MF;Wang, N;Quinn, TP
α -促黑素细胞激素（α - msh）类似物，通过位点特异性铼（Re）和锝（Tc）金属配位环化，结构表征和分析其结合存在于黑色素瘤细胞和荷瘤小鼠中的α - msh受体的能力。对B16 F1小鼠黑色素瘤细胞进行的受体结合试验结果表明，在Re掺入环状Cys(4,10), D-Phe(7)- α - msh4 -13类似物后，受体致盲亲和力降低到其原始水平的约1%。Re-peptide配合物的结构分析表明，原肽的二硫键被硫代酸盐-金属硫代酸盐环化所取代，金属结合和无金属结构的比较表明，金属配合物显著改变了受体结合核心序列的结构。金属结合位点的重新设计产生了第二代Re-peptide复合物（ReCCMSH），其受体结合亲和力为2.9 nM，比最初的Re-cu-MSH类似物高25倍。第二代Re-peptide复合物的表征表明，该肽仍然通过Re配位环化，但受体结合序列的结构不再受到限制，合成了相应的tc -99m和(ReCCMSH)-Re-188复合物，并证明其在磷酸盐缓冲盐水中稳定，对二乙烯三胺五乙酸（DTPA）和游离半胱氨酸的挑战具有稳定性。（TcCCMSH）-Tc-99m复合物表现出明显的肿瘤摄取和滞留，在小鼠肿瘤模型系统中对黑色素瘤成像有效。α - msh类似物经Tc-99m和Re-188环化得到化学稳定且具有生物活性的分子，具有潜在的黑色素瘤成像和治疗特性。
alpha-Melanocyte stimulating hormone (alpha-MSH) analogs, cyclized through site-specific rhenium (Re) and technetium (Tc) metal coordination, were structurally characterized and analyzed for their abilities to bind alpha-MSH receptors present on melanoma cells and in tumor-bearing mice. Results from receptor-binding assays conducted with B16 F1 murine melanoma cells indicated that receptor-blinding affinity was reduced to approximately 1% of its original levels after Re incorporation into the cyclic Cys(4,10), D-Phe(7)-alpha-MSH4-13 analog. Structural analysis of the Re-peptide complex showed that the disulfide bond of the original peptide was replaced by thiolate-metal-thiolate cyclization, A comparison of the metal-bound and metal-free structures indicated that metal complexation dramatically altered the structure of the receptor-binding core sequence. Redesign of the metal binding site resulted in a second-generation Re-peptide complex (ReCCMSH) that displayed a receptor-binding affinity of 2.9 nM, 25-fold higher than the initial Re-cu-MSH analog. Characterization of the second-generation Re-peptide complex indicated that the peptide was still cyclized through Re coordination, but the structure of the receptor-binding sequence was no longer constrained, The corresponding Tc-99m. and (ReCCMSH)-Re-188 complexes were synthesized and shown to be stable in phosphate-buffered saline and to challenges from diethylenetriaminepentaacetic acid (DTPA) and free cysteine, In vivo, the (TcCCMSH)-Tc-99m complex exhibited significant tumor uptake and retention and was effective in imaging melanoma in a murine-tumor model system. Cyclization of alpha-MSH analogs via Tc-99m and Re-188 yields chemically stable and biologically active molecules with potential melanoma-imaging and therapeutic properties.