Synthesis and evaluation of bivalent ligands for binding to the human melanocortin-4 receptor |
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| Institution: | 1. Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA;2. H. Lee Moffitt Cancer Center and Research Institute, Department of Cancer Imaging and Metabolism, Tampa, FL 33612, USA;1. School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of Korea;2. Department of Biological Sciences, Inha University, Incheon 402-751, Republic of Korea;3. School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea;3. From the Hematology-Oncology Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104;4. Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104,;5. the Department of Chemistry and Biochemistry and the BioFrontiers Institute, University of Colorado, Boulder, Colorado 80030, and;6. the Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158-9001;1. Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;2. School of Pharmacy, China Pharmaceutical University, Jiangsu, Nanjing 210009, China;3. School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China;1. Khlopin Radium Institute, 2-i Murinskii pr. 28, St. Petersburg 194021, Russia;2. Department of Chemistry, St. Petersburg State University, Universitetskii pr. 26, St. Petersburg 198504, Russia;3. Department of Crystallography, St. Petersburg State University, Universitetskaya nab. 7/9, St. Petersburg 199034, Russia;1. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia;2. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia;3. Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom;4. Department of Chemistry, Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, TN 37232, United States |
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| Abstract: | Membrane proteins, especially G-protein coupled receptors (GPCRs), are interesting and important theragnostic targets since many of them serve in intracellular signaling critical for all aspects of health and disease. The potential utility of designed bivalent ligands as targeting agents for cancer diagnosis and/or therapy can be evaluated by determining their binding to the corresponding receptors. As proof of concept, GPCR cell surface proteins are shown to be targeted specifically using multivalent ligands. We designed, synthesized, and tested a series of bivalent ligands targeting the over-expressed human melanocortin 4 receptor (hMC4R) in human embryonic kidney (HEK) 293 cells. Based on our data suggesting an optimal linker length of 25 ± 10 Å inferred from the bivalent melanocyte stimulating hormone (MSH) agonist, the truncated heptapeptide, referred to as MSH(7): Ac-Ser-Nle-Glu-His-D-Phe-Arg-Trp-NH2 was used to construct a set of bivalent ligands incorporating a hMC4R antagonist, SHU9119: Ac-Nle-cAsp-His-2′-D-Nal-Arg-Trp-Lys]-NH2 and another set of bivalent ligands containing the SHU9119 antagonist pharmacophore on both side of the optimized linkers. These two binding motifs within the bivalent constructs were conjoined by semi-rigid (Pro-Gly)3 units with or without the flexible poly(ethylene glycol) (PEGO) moieties. Lanthanide-based competitive binding assays showed bivalent ligands binds to the hMC4R with up to 240-fold higher affinity than the corresponding linked monovalent ligands. |
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| Keywords: | Bivalent ligands Linkers Melanocortin receptors Eu-binding assay Solid phase synthesis |
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