Discovery, affinity maturation and multimerization of small molecule ligands against human tyrosinase and tyrosinase-related protein 1. Issue 3 (13th November 2020)

• Record Type: Journal Article
• Authors: Catalano, Marco; Bassi, Gabriele; Rotondi, Giulia; Khettabi, Lyna; Dichiara, Maria; Murer, Patrizia; Scheuermann, Jörg; Soler-Lopez, Montserrat; Neri, Dario
• Is Part Of: RSC medicinal chemistry. Volume 12:Issue 3(2021)
• Page Start: 363
• Page End: 369
• Publication Date: 2020-11-13
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1039/d0md00310g
• Languages: English
• ISSNs: 2632-8682

Abstract

Abstract : A series of different strategies were oriented toward the discovery of small molecule ligands binding to the human version of tyrosinase (hTYR) and tyrosinase-related protein 1 (hTYRP1), which may represent the basis for novel treatments of melanoma. Abstract : 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.