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

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...

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Autores principales: Catalano, Marco, Bassi, Gabriele, Rotondi, Giulia, Khettabi, Lyna, Dichiara, Maria, Murer, Patrizia, Scheuermann, Jörg, Soler-Lopez, Montserrat, Neri, Dario
Formato: Online Artículo Texto
Lenguaje:English
Publicado: RSC 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130610/
https://www.ncbi.nlm.nih.gov/pubmed/34041485
http://dx.doi.org/10.1039/d0md00310g
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author Catalano, Marco
Bassi, Gabriele
Rotondi, Giulia
Khettabi, Lyna
Dichiara, Maria
Murer, Patrizia
Scheuermann, Jörg
Soler-Lopez, Montserrat
Neri, Dario
author_facet Catalano, Marco
Bassi, Gabriele
Rotondi, Giulia
Khettabi, Lyna
Dichiara, Maria
Murer, Patrizia
Scheuermann, Jörg
Soler-Lopez, Montserrat
Neri, Dario
author_sort Catalano, Marco
collection PubMed
description 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.
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spelling pubmed-81306102021-05-25 Discovery, affinity maturation and multimerization of small molecule ligands against human tyrosinase and tyrosinase-related protein 1 Catalano, Marco Bassi, Gabriele Rotondi, Giulia Khettabi, Lyna Dichiara, Maria Murer, Patrizia Scheuermann, Jörg Soler-Lopez, Montserrat Neri, Dario RSC Med Chem Chemistry 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. RSC 2020-11-13 /pmc/articles/PMC8130610/ /pubmed/34041485 http://dx.doi.org/10.1039/d0md00310g Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/
spellingShingle Chemistry
Catalano, Marco
Bassi, Gabriele
Rotondi, Giulia
Khettabi, Lyna
Dichiara, Maria
Murer, Patrizia
Scheuermann, Jörg
Soler-Lopez, Montserrat
Neri, Dario
Discovery, affinity maturation and multimerization of small molecule ligands against human tyrosinase and tyrosinase-related protein 1
title Discovery, affinity maturation and multimerization of small molecule ligands against human tyrosinase and tyrosinase-related protein 1
title_full Discovery, affinity maturation and multimerization of small molecule ligands against human tyrosinase and tyrosinase-related protein 1
title_fullStr Discovery, affinity maturation and multimerization of small molecule ligands against human tyrosinase and tyrosinase-related protein 1
title_full_unstemmed Discovery, affinity maturation and multimerization of small molecule ligands against human tyrosinase and tyrosinase-related protein 1
title_short Discovery, affinity maturation and multimerization of small molecule ligands against human tyrosinase and tyrosinase-related protein 1
title_sort discovery, affinity maturation and multimerization of small molecule ligands against human tyrosinase and tyrosinase-related protein 1
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130610/
https://www.ncbi.nlm.nih.gov/pubmed/34041485
http://dx.doi.org/10.1039/d0md00310g
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