Design, Synthesis, and Biological Studies of Efficient Multivalent Melanotropin Ligands: Tools toward Melanoma Diagnosis and Treatment
Design, Synthesis, and Biological Studies of Efficient Multivalent Melanotropin Ligands: Tools toward Melanoma Diagnosis and Treatment
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DOI：
10.1021/jm2009937
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发表时间：
2011-10-27
影响因子：
7.3
通讯作者：
Hruby, Victor J.
中科院分区：
文献类型：
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作者：
Brabez, Nabila;Lynch, Ronald M.;Hruby, Victor J.
为了实现早期检测和特异性癌症治疗，我们建议使用多价相互作用，其中一系列结合事件导致亲和力增加，从而提高选择性。利用促黑素（MSH）配体，我们的目标是靶向过度表达黑素皮质素受体的黑色素瘤细胞。在这项研究中，我们报道了新的三价配体承载MSH配体的设计和高效合成。在细胞模型上对这些多聚体进行评估，以过度表达黑素皮质素4受体（MC4R），结果显示与单体相比，这些多聚体的结合能力增加了350倍，产生了从微摩尔亲和力配体开始的具有纳米摩尔亲和力的三价结构。我们还研究了环磷酸腺苷（cAMP）的产生，从而对多价化合物对转导机制的影响有了更多的了解。
To achieve early detection and specific cancer treatment, we propose the use of multivalent interactions in which a series of binding events leads to increased affinity and consequently to selectivity. Using melanotropin (MSH) ligands, our aim is to target melanoma cells which overexpress melanocortin receptors. In this study, we report the design and efficient synthesis of new trivalent ligands bearing MSH ligands. Evaluation of these multimers on a cell model engineered to overexpress melanocortin 4 receptors (MC4R) showed up to a 350-fold increase in binding compared to the monomer, resulting in a trivalent construct with nanomolar affinity starting from a micromolar affinity ligand. Cyclic adenosine monophosphate (cAMP) production was also investigated, leading to more insights into the effects of multivalent compounds on transduction mechanisms.