Amphiphilic 3′‐Peptidyl‐RNA Conjugates

Terenzi, Silvia; Biala, Ewa; Nguyen-Trung, Nhat Quang; Strazewski, Peter

doi:10.1002/ange.200350926

Cited by 16 publications

(11 citation statements)

References 33 publications

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“…These novel solid supports were readily accessible from the key precursor 3′‐azido‐3′‐deoxyadenosine ( 1 ), for which we have previously introduced a straightforward synthesis 10. Coupling of N ‐Fmoc‐ and O ‐TBDMS‐protected L ‐serine or L ‐threonine under Staudinger–Vilarrasa conditions16, 17 furnished the amino acid linked building blocks 2 and 3 (Scheme ). These derivatives were further transformed into pentafluorophenyl active esters by using adipic acid bis(pentafluorophenyl)ester to generate a tether that allowed coupling to amino‐modified polystyrene yielding the desired 3′‐aminoacylamino‐3′‐deoxyadenosine‐functionalized solid supports 4 and 5 .…”

Section: Resultsmentioning

confidence: 99%

“…The structural complexity of the amino acid-RNA and peptide-RNA conjugates, in particular the 3'-peptidyl-tRNA mimics, present a series of challenges for de novo synthesis. [10][11][12][13][14][15][16][17][18][19][20][21] The importance of tRNA conjugates in probing fundamental biological enzymatic mechanisms argues that the development of efficient synthetic protocols for such ligands is warranted.…”

Section: Introductionmentioning

confidence: 99%

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The Synthesis of Methylated, Phosphorylated, and Phosphonated 3′‐Aminoacyl‐tRNA^Sec Mimics

Rigger¹,

Schmidt

Holman

et al. 2013

Chemistry A European J

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The twenty first amino acid, selenocysteine (Sec), is the only amino acid that is synthesized on its cognate transfer RNA (tRNASec) in all domains of life. The multistep pathway involves O-phosphoseryl-tRNA:selenocysteinyl-tRNA synthase (SepSecS), an enzyme that catalyzes the terminal chemical reaction during which the phosphoseryl–tRNASec intermediate is converted into selenocysteinyl-tRNASec. The SepSecS architecture and the mode of tRNASec recognition have been recently determined at atomic resolution. The crystal structure provided valuable insights that gave rise to mechanistic proposals that could not be validated because of the lack of appropriate molecular probes. To further improve our understanding of the mechanism of the biosynthesis of selenocysteine in general and the mechanism of SepSecS in particular, stable tRNASec substrates carrying aminoacyl moieties that mimic particular reaction intermediates are needed. Here, we report on the accurate synthesis of methylated, phosphorylated, and phosphonated serinyl-derived tRNASec mimics that contain a hydrolysis-resistant ribose 3′-amide linkage instead of the natural ester bond. The procedures introduced allow for efficient site-specific methylation and/or phosphorylation directly on the solid support utilized in the automated RNA synthesis. For the preparation of (S)-2-amino-4-phosphonobutyric acid–oligoribonucleotide conjugates, a separate solid support was generated. Furthermore, we developed a three-strand enzymatic ligation protocol to obtain the corresponding full-length tRNASec derivatives. Finally, we developed an electrophoretic mobility shift assay (EMSA) for rapid, qualitative characterization of the SepSecS-tRNA interactions. The novel tRNASec mimics are promising candidates for further elucidation of the biosynthesis of selenocysteine by X-ray crystallography and other biochemical approaches, and could be attractive for similar studies on other tRNA-dependent enzymes.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Synthesis of Methylated, Phosphorylated, and Phosphonated 3′‐Aminoacyl‐tRNA^Sec Mimics

Rigger¹,

Schmidt

Holman

et al. 2013

Chemistry A European J

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“…So far, most low-molecular-weight mimics for peptidyl-tRNA termini reported in the literature have relied on puromycin (Pmn) as the crucial linker unit, [13] while only few have utilized 3'-amino-or very recently, 3'-triazolyladenosine derivatives. [14,15] For instance, CCPmn, ACCPmn, and derivatives thereof were synthesized to represent the CCA-amino acid terminus of amino acid charged tRNA (Figure 3). [13a,b] Since these compounds possess a stable 3'-amide linkage they were successfully applied in soaking experiments with ribosome crystals, and subsequent X-ray structure determination of the co-crystals provided insight into the interactions between tRNA termini and the PTC, and the process of peptide bond formation.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2009

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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.

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“…[1] Full-size peptidyl tRNA is difficult to prepare synthetically, but analogs with more stable linkages have been synthesized. [2][3][4][5][6] Another class of covalently linked species is that of nucleopeptides, with a phosphodiester link between the side chain of an amino acid and a short oligoribonucleotide. [7,8] They are models for structures found in some viruses.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Peptido RNAs from Unprotected Peptides and Oligoribonucleotides via Coupling in Aqueous Solution

2020

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Peptido RNAs are hybrid molecules with a phosphoramidate link between the N‐terminus of a peptide and the 5'‐phosphate of an oligoribonucleotide. Such species are formed in spontaneous co‐oligomerizations of amino acids and ribonucleotides in aqueous condensation buffer. To shed light on the properties of these fascinating molecules, a synthetic method for their preparation in monodisperse form is needed. Herein, we report how peptido RNAs can be prepared via solution‐phase coupling of unprotected peptides and oligoribonucleotides in aqueous solution. The preferred protocol uses pre‐activation of the 5'‐phosphate of the RNA as an imidazolide at pH 6.5, followed by precipitation and coupling to the peptide at pH 8 with an organocatalyst. The procedure gave peptido RNAs from water‐soluble peptides and synthetic oligoribonucleotides in up to 68 % yield. The method is convenient and inexpensive and can produce NMR quantities, opening the door to the systematic exploration of the chemistry of peptido RNAs.

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Amphiphilic 3′‐Peptidyl‐RNA Conjugates

Cited by 16 publications

References 33 publications

The Synthesis of Methylated, Phosphorylated, and Phosphonated 3′‐Aminoacyl‐tRNA^Sec Mimics

The Synthesis of Methylated, Phosphorylated, and Phosphonated 3′‐Aminoacyl‐tRNA^Sec Mimics

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

Synthesis of Peptido RNAs from Unprotected Peptides and Oligoribonucleotides via Coupling in Aqueous Solution

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Amphiphilic 3′‐Peptidyl‐RNA Conjugates

Cited by 16 publications

References 33 publications

The Synthesis of Methylated, Phosphorylated, and Phosphonated 3′‐Aminoacyl‐tRNASec Mimics

The Synthesis of Methylated, Phosphorylated, and Phosphonated 3′‐Aminoacyl‐tRNASec Mimics

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

Synthesis of Peptido RNAs from Unprotected Peptides and Oligoribonucleotides via Coupling in Aqueous Solution

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Product

Resources

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The Synthesis of Methylated, Phosphorylated, and Phosphonated 3′‐Aminoacyl‐tRNA^Sec Mimics

The Synthesis of Methylated, Phosphorylated, and Phosphonated 3′‐Aminoacyl‐tRNA^Sec Mimics