Discovery, affinity maturation and multimerization of small molecule ligands against human tyrosinase and tyrosinase-related protein 1,RSC Medicinal Chemistry

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Discovery, affinity maturation and multimerization of small molecule ligands against human tyrosinase and tyrosinase-related protein 1
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2020-11-13 , DOI: 10.1039/d0md00310g
Marco Catalano ₁ , Gabriele Bassi ₁ , Giulia Rotondi _{1,

2} , Lyna Khettabi _{3,

4} , Maria Dichiara ₁ , Patrizia Murer ₁ , Jörg Scheuermann ₁ , Montserrat Soler-Lopez ₃ , Dario Neri ₁

Affiliation

Human tyrosinase (hTYR) and tyrosinase-related protein 1 (hTYRP1) are closely-related enzymes involved in the synthesis of melanin, which are selectively expressed in melanocytes and, in a pathological context, in melanoma lesions. We used a previously described tyrosinase inhibitor (Thiamidol™) and DNA-encoded library technology for the discovery of novel hTYR and hTYRP1 ligands, that could be used as vehicles for melanoma targeting. Performing de novo selections with DNA-encoded libraries, we discovered novel ligands capable of binding to both hTYR and hTYRP1. More potent ligands were obtained by multimerizing Thiamidol™ moieties, leading to homotetrameric structures that avidly bound to melanoma cells, as revealed by flow cytometry. These findings suggest that melanoma lesions may, in the future, be targeted not only by monoclonal antibody reagents but also by small organic ligands.

中文翻译：

针对人酪氨酸酶和酪氨酸酶相关蛋白 1 的小分子配体的发现、亲和力成熟和多聚化

人酪氨酸酶 (hTYR) 和酪氨酸酶相关蛋白 1 (hTYRP1) 是与黑色素合成密切相关的酶，它们在黑色素细胞中选择性表达，在病理情况下，在黑色素瘤病变中选择性表达。我们使用先前描述的酪氨酸酶抑制剂 (Thiamidol™) 和 DNA 编码库技术来发现新的 hTYR 和 hTYRP1 配体，它们可用作黑色素瘤靶向的载体。从头表演通过 DNA 编码文库的选择，我们发现了能够与 hTYR 和 hTYRP1 结合的新型配体。如流式细胞术所揭示的，通过多聚化 Thiamidol™ 部分获得更有效的配体，从而产生与黑色素瘤细胞紧密结合的同源四聚体结构。这些发现表明，在未来，黑色素瘤病变可能不仅会被单克隆抗体试剂靶向，而且还会被小的有机配体靶向。

更新日期：2021-01-12

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