Non‐Hydrolyzable RNA–Peptide Conjugates: A Powerful Advance in the Synthesis of Mimics for 3′‐Peptidyl tRNA Termini

Abstract

Translation of specific small peptides on the ribosome can confer resistance to macrolide antibiotics. To reveal the molecular details of this and related phenomena, stable RNA-peptide conjugates that mimic peptidyl-tRNA would be desirable, especially for ribosome structural biology. A flexible solid-phase synthesis strategy now allows efficient access to these highly requested derivatives without restriction on the RNA and peptide sequences.

Binding of Macrolide Antibiotics Leads to Ribosomal Selection against Specific Substrates Based on Their Charge and Size

“…In order to substantiate this conclusion, we followed the kinetics of peptide bond formation between the donor MRL-tRNA and different model acceptor substrates. For these experiments, we synthesized chemically stable substrates mimicking the aminoacyl-tRNA acceptor end (Graber et al, 2010; Moroder et al, 2009) (Table 1). In these aminoacyl-tRNA analogs with the general structure ACCA-X, various amino acid residues (X) were linked to the 3′ carbon atom of the universal tRNA sequence ACCA via a stable amide bond (Supplementary Information).…”

Small Molecule Binding, Docking, and Characterization of the Interaction between Pth1 and Peptidyl-tRNA

“…This has been particularly helpful for RNA structures [40,41]. Considerable progress has been made with combining tRNA and peptides [42,43], though scale up has been problematic and/or expensive. Continued efforts will help understand the intricate workings of Pth1 enzymes and hopefully fulfill their pharmacological potential.…”

Preparation of modified long-mer RNAs and analysis of FMN binding to theypaAaptamer fromB. subtilis

“…4C) and a 3′-azido nucleoside linked to the solid support. The latter is not commercially available and therefore was synthesized starting from arabinoadenosine, 30 followed by immobilization as described (Fig. 4D).…”

“…Epimerization of the arabinose to ribose was performed using the protocol described by Micura and coworkers. 30 The protected 3′-azido-adenosine was linked to the solid support as described. 30 Briefly, the 2′-hydroxyl group was converted to an adipinic-acid-ester providing a second functionalized pentafluorophenylester to be coupled onto amino functionalized polysterene (Fig.…”