Thiol Catalysis of Selenosulfide Bond Cleavage by a Triarylphosphine

Firstova, Olga; Melnyk, Oleg; Diemer, Vincent

doi:10.1021/acs.joc.2c00934

Cited by 3 publications

(4 citation statements)

References 28 publications

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“…In the presence of TCEP (tris(2-carboxyethyl)phosphine), we showed that the rate of the reaction was independent of the phosphine, the thiol additive and the SetCys peptide concentrations [5]. This result points towards a mechanism in which the Se-S bond is directly and quickly reduced by the phosphine (Figure 2b, path a).…”

Section: Resultsmentioning

confidence: 88%

“…The ring-opening of SetCys is so fast in these strong reducing conditions that the rate of the whole process is dictated by the subsequent cleavage of the selenoethyl appendage. The situation is clearly different when a less reactive phosphine such as TPPTS (3,3′,3′′phosphanetriyltris(benzenesulfonic acid) trisodium salt) was used as reductant [5]. We found that the rate of the SetCys to Cys conversion depends in this case on the aryl phosphine concentration (Figure 2a, graph 1), and this up to 35 mM, a concentration above which the reduction process involving TPPTS is no longer rate limiting.…”

Section: Resultsmentioning

confidence: 88%

See 1 more Smart Citation

Expanding the Protein Chemical Synthesis Toolbox with N- Selenoethyl Cysteine

Diemer¹,

Firstova²,

Agouridas³

et al. 2022

Proceedings of the 36th European and the 12th International Peptide Symposium

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Section: Resultsmentioning

confidence: 88%

Section: Resultsmentioning

confidence: 88%

Expanding the Protein Chemical Synthesis Toolbox with N- Selenoethyl Cysteine

Diemer¹,

Firstova²,

Agouridas³

et al. 2022

Proceedings of the 36th European and the 12th International Peptide Symposium

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“…A plausible explanation for this observation is based on a mechanism proposed by Melnyk et al for their N-selenoethyl cysteine redox switch system. [22] There, an intermolecular nucleophilic attack of the selenolate leads to cleavage of the carbon-nitrogen bond. In response to this observation, we reduced the amount of TCEP to 0.5 equiv in relation to the peptide and confirmed that this minimizes undesired SeAUX removal.…”

Section: Ligation Efficiency Of Gly(seaux)mentioning

confidence: 99%

Light‐Cleavable Auxiliary for Diselenide–Selenoester Ligations of Peptides and Proteins

Schrems

Kravchuk

Niederacher

et al. 2023

Chemistry A European J

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Diselenide–selenoester ligations are increasingly used for the synthesis of proteins. Excellent ligation rates, even at low concentrations, in combination with mild and selective deselenization conditions can overcome some of the most severe challenges in chemical protein synthesis. Herein, the versatile multicomponent synthesis and application of a new ligation auxiliary that combines a photocleavable scaffold with the advantages of selenium‐based ligation strategies are presented. Its use was investigated with respect to different ligation junctions and describe a novel para‐methoxybenzyl deprotection reaction for the selenol moiety. The glycine‐based auxiliary enabled successful synthesis of the challenging target protein G‐CSF.

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“…The quest for a redox-sensitive Cys surrogate came again on stage when we discovered that the selenium analogue of SutCys called SetCys can spontaneously lose its selenoethyl arm upon reduction by TCEP or 3,3′,3″-phosphanetriyltris(benzenesulfonic acid) trisodium salt (TPPTS, Figure ). , We showed that the loss of the selenoethyl arm proceeds by an ionic mechanism whose rate is the fastest at pH 6–6.5, i.e., a pH compatible with NCL or SEA-mediated ligation. Our investigations strongly suggest that the cleavage of the C–N bond proceeds through an intramolecular substitution of the protonated SetCys alpha amino group by the selenoate as depicted in Figure b.…”

Section: The Search For a Redox-controlled Cys Surrogatementioning

confidence: 99%

Redox-Controlled Chemical Protein Synthesis: Sundry Shades of Latency

et al. 2022

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Conspectus The last two decades have witnessed the rise in power of chemical protein synthesis to the point where it now constitutes an established corpus of synthetic methods efficiently complementing biological approaches. One factor explaining this spectacular evolution is the emergence of a new class of chemoselective reactions enabling the formation of native peptide bonds between two unprotected peptidic segments, also known as native ligation reactions. In recent years, their application has fueled the production of homogeneous batches of large and highly decorated protein targets with a control of their composition at the atomic level. In doing so, native ligation reactions have provided the means for successful applications in chemical biology, medicinal chemistry, materials science, and nanotechnology research. The native chemical ligation (NCL) reaction has had a major impact on the field by enabling the chemoselective formation of a native peptide bond between a C-terminal peptidyl thioester and an N-terminal cysteinyl peptide. Since its introduction in 1994, the NCL reaction has been made the object of significant improvements and its scope and limitations have been thoroughly investigated. Furthermore, the diversification of peptide segment assembly strategies has been essential to access proteins of increasing complexity and has had to overcome the challenge of controlling the reactivity of ligation partners. One hallmark of NCL is its dependency on thiol reactivity, including for its catalysis. While Nature constantly plays with the redox properties of biological thiols for the regulation of numerous biochemical pathways, such a control of reactivity is challenging to achieve in synthetic organic chemistry and, in particular, for those methods used for assembling peptide segments by chemical ligation. This Account covers the studies conducted by our group in this area. A leading theme of our research has been the conception of controllable acyl donors and cysteine surrogates that place the chemoselective formation of amide bonds by NCL-like reactions under the control of dichalcogenide-based redox systems. The dependency of the redox potential of dichalcogenide bonds on the nature of the chalcogenides involved (S, Se) has appeared as a powerful means for diversifying the systems, while allowing their sequential activation for protein synthesis. Such a control of reactivity mediated by the addition of harmless redox additives has greatly facilitated the modular and efficient preparation of multiple targets of biological relevance. Taken together, these endeavors provide a practical and robust set of methods to address synthetic challenges in chemical protein synthesis.

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Thiol Catalysis of Selenosulfide Bond Cleavage by a Triarylphosphine

Cited by 3 publications

References 28 publications

Expanding the Protein Chemical Synthesis Toolbox with N- Selenoethyl Cysteine

Expanding the Protein Chemical Synthesis Toolbox with N- Selenoethyl Cysteine

Light‐Cleavable Auxiliary for Diselenide–Selenoester Ligations of Peptides and Proteins

Redox-Controlled Chemical Protein Synthesis: Sundry Shades of Latency

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