Design of a True Bivalent Ligand with Picomolar Binding Affinity for a G Protein-Coupled Receptor Homodimer

被引:34
作者
Pulido, Daniel [1 ,2 ,8 ]
Casado-Anguera, Veronica [3 ,4 ,5 ]
Perez-Benito, Laura [6 ]
Moreno, Estefania [3 ,4 ,5 ]
Cordomei, Arnau [6 ]
Lopez, Laura [6 ]
Cortes, Antoni [3 ,4 ,5 ]
Ferre, Sergi [7 ]
Pardo, Leonardo [6 ]
Casado, Vicent [3 ,4 ,5 ]
Royo, Miriam [1 ,2 ,8 ]
机构
[1] Biomed Res Networking Ctr Bioengn Biomat & Nanome, Biomat & Nanomed, Barcelona Sci Pk, Barcelona 08028, Spain
[2] Combinatorial Chem Unit, Barcelona Sci Pk, Barcelona 08028, Spain
[3] Univ Barcelona, Dept Biochem & Mol Biomed, Fac Biol, E-08028 Barcelona, Spain
[4] Biomed Res Networking Ctr Neurodegenerat Dis CIBE, Barcelona 08028, Spain
[5] Univ Barcelona, Inst Biomed, E-08028 Barcelona, Spain
[6] Univ Autonoma Barcelona, Lab Computat Med, Biostat Unit, Fac Med, Bellaterra 08193, Spain
[7] NIDA, Integrat Neurobiol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA
[8] Inst Adv Chem Catalonia IQAC CSIC, Barcelona 08034, Spain
关键词
ALLOSTERIC INTERACTIONS; CRYSTAL-STRUCTURE; ADENOSINE A(2A); HETEROMERS; AGONISTS; COMPLEX; SELECTIVITY; ANTAGONISTS; OLIGOMERS; TARGETS;
D O I
10.1021/acs.jmedchem.8b01249
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Bivalent ligands have emerged as chemical tools to study G protein-coupled receptor dimers. Using a combination of computational, chemical, and biochemical tools, here we describe the design of bivalent ligand 13 with high affinity (K-DB1( )= 21 pM) for the dopamine D-2 receptor (D2R) homodimer. Bivalent ligand 13 enhances the binding affinity relative to monovalent compound 15 by 37-fold, indicating simultaneous binding at both protomers. Using synthetic peptides with amino acid sequences of transmembrane (TM) domains of D2R, we provide evidence that TM6 forms the interface of the homodimer. Notably, the disturber peptide TAT-TM6 decreased the binding of bivalent ligand 13 by 52-fold and had no effect on monovalent compound 15, confirming the D2R homodimer through TM6 ex vivo. In conclusion, by using a versatile multivalent chemical platform, we have developed a precise strategy to generate a true bivalent ligand that simultaneously targets both orthosteric sites of the D2R homodimer.
引用
收藏
页码:9335 / 9346
页数:12
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