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Electrophilic RNA for Peptidyl‐RNA Synthesis and Site‐Specific Cross‐Linking with tRNA‐Binding Enzymes
Author(s) -
Fonvielle Matthieu,
Sakkas Nicolas,
Iannazzo Laura,
Le Fournis Chloé,
Patin Delphine,
MenginLecreulx Dominique,
ElSagheer Afaf,
Braud Emmanuelle,
Cardon Sébastien,
Brown Tom,
Arthur Michel,
EtheveQuelquejeu Mélanie
Publication year - 2016
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201606843
Subject(s) - rna , electrophile , pentapeptide repeat , chemistry , transfer rna , enzyme , ribozyme , combinatorial chemistry , cytidine , biochemistry , peptidoglycan , stereochemistry , catalysis , peptide , gene
RNA functionalization is challenging due to the instability of RNA and the limited range of available enzymatic reactions. We developed a strategy based on solid phase synthesis and post‐functionalization to introduce an electrophilic site at the 3′ end of tRNA analogues. The squarate diester used as an electrophile enabled sequential amidation and provided asymmetric squaramides with high selectivity. The squaramate‐RNAs specifically reacted with the lysine of UDP‐MurNAc‐pentapeptide, a peptidoglycan precursor used by the aminoacyl‐transferase FemX Wv for synthesis of the bacterial cell wall. The peptidyl‐RNA obtained with squaramate‐RNA and unprotected UDP‐MurNAc‐pentapeptide efficiently inhibited FemX Wv . The squaramate unit also promoted specific cross‐linking of RNA to the catalytic Lys of FemX Wv but not to related transferases recognizing different aminoacyl‐tRNAs. Thus, squaramate‐RNAs provide specificity for cross‐linking with defined groups in complex biomolecules due to its unique reactivity.