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

Autor:	Catalano M; Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich) Vladimir-Prelog-Weg 4 CH-8093 Zürich Switzerland dario.neri@pharma.ethz.ch., Bassi G; Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich) Vladimir-Prelog-Weg 4 CH-8093 Zürich Switzerland dario.neri@pharma.ethz.ch., Rotondi G; Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich) Vladimir-Prelog-Weg 4 CH-8093 Zürich Switzerland dario.neri@pharma.ethz.ch.; Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome P.le A. Moro 5 00185 Rome Italy., Khettabi L; Structural Biology Group, European Synchrotron Radiation Facility 71 Avenue des Martyrs 38000 Grenoble France.; CNRS, DCM, Université Grenoble Alpes 38000 Grenoble France., Dichiara M; Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich) Vladimir-Prelog-Weg 4 CH-8093 Zürich Switzerland dario.neri@pharma.ethz.ch., Murer P; Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich) Vladimir-Prelog-Weg 4 CH-8093 Zürich Switzerland dario.neri@pharma.ethz.ch., Scheuermann J; Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich) Vladimir-Prelog-Weg 4 CH-8093 Zürich Switzerland dario.neri@pharma.ethz.ch., Soler-Lopez M; Structural Biology Group, European Synchrotron Radiation Facility 71 Avenue des Martyrs 38000 Grenoble France., Neri D; Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich) Vladimir-Prelog-Weg 4 CH-8093 Zürich Switzerland dario.neri@pharma.ethz.ch.
Jazyk:	angličtina
Zdroj:	RSC medicinal chemistry [RSC Med Chem] 2020 Nov 13; Vol. 12 (3), pp. 363-369. Date of Electronic Publication: 2020 Nov 13.
DOI:	10.1039/d0md00310g
Abstrakt:	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. Competing Interests: The authors declare the following competing financial interest(s): D. N. is a cofounder and shareholder of Philochem AG. (This journal is © The Royal Society of Chemistry.)
Databáze:	MEDLINE
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