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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 FemXWv for synthesis of the bacterial cell wall. The peptidyl-RNA obtained with squaramate-RNA and unprotected UDP-MurNAc-pentapeptide efficiently inhibited FemXWv . The squaramate unit also promoted specific cross-linking of RNA to the catalytic Lys of FemXWv 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.

Original publication

DOI

10.1002/anie.201606843

Type

Journal article

Journal

Angew Chem Int Ed Engl

Publication Date

17/10/2016

Volume

55

Pages

13553 - 13557

Keywords

Fem transferases, RNA modifications, crosslinking, post-functionalization, squarates, Aminoacyltransferases, Cross-Linking Reagents, Models, Molecular, Molecular Conformation, Peptides, RNA, RNA, Transfer, Uridine Diphosphate N-Acetylmuramic Acid