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

Abstract

Die Translation kleiner Peptide am Ribosom kann diesem eine Resistenz gegen Macrolidantibiotika verleihen. Zur Aufklärung dieses und ähnlicher Phänomene sind stabile RNA‐Peptid‐Konjugate, die Peptidyl‐tRNA imitieren, wünschenswert, besonders für die strukturbiologische Untersuchung von Ribosomen. Eine flexible Festphasensynthesestrategie macht diese Konjugate nun in effizienter Weise zugänglich, ohne Beschränkungen bezüglich der RNA‐ und Peptidsequenz.

Selective Desulfurization Significantly Expands Sequence Variety of 3′‐Peptidyl–tRNA Mimics Obtained by Native Chemical Ligation

“…Such conjugates have resisted direct access by solid-phase synthesis in which both peptide and RNA are assembled on the same functionalized solid support, followed by cleavage and deprotection of the whole conjugate 6a, d. We furthermore underline that the conditions elaborated here for desulfurization are compatible with methionine, which carries a thioether moiety that turned out to be sufficiently stable.…”

“…The total syntheses of 3′-aminoacyl- and 3′-peptidyl-RNA represent substantive challenges for organic chemists;2c,d therefore, a central focus of our research is the de novo synthesis of these derivatives 6. We have recently elaborated a convergent strategy that involves native chemical ligation (NCL) of 3′-cysteinylamino-3′-deoxy-RNA and peptide thioesters 7.…”

“…We decided in favor of β,β-dimethylcysteine (penicillamine, Pen)13 rather than γ-thiol valine as a precursor12 because of its commercial availability with various protection patterns. We consequently synthesized the novel 3′-(β,β-dimethylcysteinyl)amino-3′-deoxyadenosine-modified solid support (Supporting Information) for RNA solid-phase synthesis, on the basis of a previously elaborated route for generating 3′-aminoacylamino-3′-deoxyadenosine derivatives 6a. After having prepared 3′-penicillaminyl-RNA and the corresponding peptide ABT ester, the ligation–desulfurization protocol developed herein furnished conjugate 5′-G 3 UGAU 3 CGAUCAC 3 AC 2 A-3′-NH-VGFFM-NH 2 8 in low but acceptable yield, leaving room for further optimization; unreacted and desulfurized starting material were the major byproducts.…”

Synthesis of Peptide‐Oligonucleotide Conjugates Using a Heterobifunctional Crosslinker

“…Several methods exist to conjugate polypeptides to synthetic DNA and RNA (Roberts and Szostak, 1997; Venkatesan and Kim, 2006; Moroder, Steger et al, 2009). The most commonly used method of peptide-oligonucleotide construction is in-line solid phase synthesis.…”

Efficient Access to Nonhydrolyzable Initiator tRNA Based on the Synthesis of 3′‐Azido‐3′‐Deoxyadenosine RNA

“…[7] This compound was transformed into the pentafluorophenyl (Pfp) adipic acid ester 6 and finally into the functionalized solid support 7 (Scheme 2 A). [7] This compound was transformed into the pentafluorophenyl (Pfp) adipic acid ester 6 and finally into the functionalized solid support 7 (Scheme 2 A).…”