Conversion of 4 to the corresponding ribofuranosyl bromide allowed efficient access to C, A, and G analogues. Ribofuranose 4 glycosylated bis(trimethylsilyl)uracil directly, giving difluoromethyluridine 7 efficiently after deprotection. The key steps included nucleophilic addition of difluoromethyl phenyl sulfone to 2-ketoribose 2 followed by mild and efficient reductive desulfonation. We constructed the glycosylating agent 4 in three steps from 1,3,5-tri-O-benzoyl-α-d-ribofuranose 1. Here we describe synthetic entry into a new subclass of these analogues, 2‘-C-β-difluoromethylribonucleosides. These findings yield valuable insights for engineering of Fabs as RNA-binding modules and facilitate further development of Fabs as possible therapeutic drugs and biochemical tools to explore RNA biology.read more read lessĪbstract: Nucleosides bearing a branched ribose have significant promise as therapeutic agents and biotechnological and biochemical tools. The Fab-RNA interface also differs significantly from Fab-protein interfaces in amino acid composition and light-chain participation. The crystal structure reveals that the Fab achieves specific RNA binding on a shallow surface with complementarity-determining region (CDR) sequence diversity, length variability, and main-chain conformational plasticity. Capability in phasing and crystal contact formation suggests that the Fab provides a potentially valuable crystal chaperone for RNA. We have solved the crystal structure of the first Fab-RNA complex at 1.95 A. Here we have developed a robust approach using a synthetic phage-display library to select specific antigen-binding fragments (Fabs) targeting a large functional RNA. However, knowledge of RNA-binding antibodies and their application in the ever-growing RNA field is lacking. Abstract: Antibodies that bind protein antigens are indispensable in biochemical research and modern medicine.
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