Abstract
FK506-binding proteins (FKBP) 51 and 52 are cochaperones that modulate the signal transduction of steroid hormone receptors. Single nucleotide polymorphisms in the gene encoding FKBP51 have been associated with a variety of psychiatric disorders. Rapamycin and FK506 are two macrocyclic natural products, which tightly bind to most FKBP family members, including FKBP51 and FKBP52. A bioisosteric replacement of the α-ketoamide moiety of rapamycin and FK506 with a sulfonamide was envisaged with the retention of the conserved hydrogen bonds. A focused solid support-based synthesis protocol was developed, which led to ligands with submicromolar affinity for FKBP51 and FKBP52. The molecular binding mode for one sulfonamide analogue was confirmed by X-ray crystallography.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Crystallography, X-Ray
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Fluorescence Polarization
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Humans
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Magnetic Resonance Spectroscopy
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Molecular Structure
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Pipecolic Acids / chemical synthesis*
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Pipecolic Acids / chemistry
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Pipecolic Acids / pharmacology
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Protein Binding
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Spectrometry, Mass, Electrospray Ionization
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis*
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Sulfonamides / chemistry
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Sulfonamides / pharmacology
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Tacrolimus / analogs & derivatives*
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Tacrolimus / chemical synthesis
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Tacrolimus / chemistry
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Tacrolimus / pharmacology
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Tacrolimus Binding Proteins / antagonists & inhibitors
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Tacrolimus Binding Proteins / metabolism*
Substances
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Pipecolic Acids
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Sulfonamides
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Tacrolimus Binding Proteins
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tacrolimus binding protein 4
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tacrolimus binding protein 5
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Tacrolimus