Direct and quantitative analysis of tRNA acylation using intact tRNA liquid chromatography–mass spectrometry

Nature Protocols, Год журнала: 2025, Номер unknown

Опубликована: Янв. 6, 2025

Язык: Английский

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Peptide Backbone Editing via Post-Translational O to C Acyl Shift

Journal of the American Chemical Society, Год журнала: 2025, Номер unknown

Опубликована: Фев. 11, 2025

Despite tremendous efforts to engineer translational machinery, replacing the encoded peptide backbone with new-to-nature structures remains a significant challenge. C, H, O, and N are elements of life, yet ribosomes capable forming only C–N bonds as amides, C–O esters, C–S thioesters. There is no current strategy site-selectively form C–C ketones embedded in backbones ribosomal products. As an alternative direct bond formation, here we report that peptides containing dehydrolactic acid motif rapidly isomerize generate backbone-embedded α,γ-diketoamides via spontaneous formal O C acyl shift rearrangement. The can be introduced into ribosomally or solid-phase synthesis using α-hydroxyphenylselenocysteine followed by oxidation. Subsequent incubation at physiological pH produces α,γ-diketoamide diversified variety nucleophiles, including hydrazines hydroxylamines, pyrazoles oximes, respectively. All these groups remain directly within polypeptide backbone. This general for editing, predicated on intricate cascade rearrangements, provides first nonenzymatic example reaction take place products so-produced easily protein-like materials heterocycles. Application this editing should accelerate discovery genetically molecules whose properties more closely resemble those bioactive natural

Язык: Английский

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Chemo-ribosomal synthesis of atropisomeric and macrocyclic peptides with embedded quinolines

Опубликована: Июнь 10, 2024

Expanding the chemical and structural complexity of genetically encoded peptides remains a challenge in peptide therapeutics discovery. Here we report that linear with reactive β- or γ-keto amide at their N-termini can be synthesized ribosomally using vitro translation methods. We show carrying an N-terminal β-keto converted into diverse heterocyclic quinoline-peptide hybrids via Friedländer reactions variety 2-aminoarylcarbonyl co-substrates. Reactions appropriately substituted 2-aminobenzophenones generated stable biaryl atropisomeric axes. In vitro-translated both internal 2-aminoacetophenone motif undergo intramolecular macrocyclization embed quinoline pharmacophore directly within macrocyclic backbone. The introduction ketide building blocks materials post-translational derivatization carbonyl chemistry simultaneously expands diversity provides paradigm for programmed synthesis peptide-derived more closely resemble complex natural products.

Язык: Английский

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Ribosomal Synthesis of Ketone-containing Peptide Backbone via O to C Acyl Shift

Опубликована: Июль 31, 2024

Despite tremendous efforts to engineer translational machinery, replacing the encoded peptide backbone with new-to-Nature structures remains a significant and largely unmet challenge. C, H, O, N are elements of life, yet ribosomes only capable forming C–N bonds as amides, C–O esters, C–S thioesters; there is no current strategy form C–C ketones embedded in ribosomal products. We discovered that peptides containing dehydrolactic acid motif rapidly isomerize generate backbone-embedded α,γ-diketoamide via spontaneous formal O C acyl shift. The can be introduced into ribosomally or solid-phase synthesis using α-hydroxy phenylselenocysteine followed by oxidation. Subsequent incubation at physiological pH produces an diversified variety nucleophiles, including hydrazines hydroxylamines pyrazoles oximes, respectively. All these groups remain directly within polypeptide backbone. This general strategy, predicated on intricate cascade rearrangements, provides first example bond reaction take place backbone, well for generating protein-like materials diverse, heterocycles. genetically encoded, new-to-nature biopolymers produced should accelerate discovery molecules whose properties better resemble those bioactive natural

Язык: Английский

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A stereodivergent multicomponent approach for the synthesis of C–N atropisomeric peptide analogues

Chemical Science, Год журнала: 2024, Номер unknown

Опубликована: Янв. 1, 2024

Four-component reactions at room temperature delivered C–N atropisomeric peptide analogues possessing both central and axial chirality with complete diastereocontrol. Reactions elevated selectively afforded the other diastereoisomer.

Язык: Английский

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