Thiazolidine-Protected β-Thiol Asparagine: Applications in One-Pot Ligation–Desulfurization Chemistry

Sayers, Jessica; Thompson, Robert E.; Perry, Kristen J.; Malins, Lara R.; Payne, Richard J.

doi:10.1021/acs.orglett.5b02468

Cited by 33 publications

(24 citation statements)

References 40 publications

(13 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This has led to the synthesis of thiolated amino acids. To date, syntheses of several thiolated amino acid building blocks, including Asp, Asn, Arg, Glu, Gln, Leu, Lys, Pro, Phe, Thr, Trp, and Val, have been reported (Figure ), and these were incorporated into peptides suitable for synthesizing native proteins by NCL.…”

Section: Native Chemical Ligation (Ncl)mentioning

confidence: 99%

Chemical Protein Synthesis by Native Chemical Ligation and Variations Thereof

et al. 2019

View full text Add to dashboard Cite

For a long time, the total synthesis of proteins was considered as a “mission impossible” because of the tedious and complex synthetic steps and demanding purification processes. However, with the development of modern synthetic methodologies, many protein syntheses have now been reported. More importantly, through chemical synthesis, desired modifications can be installed to target proteins precisely, which is a major advantage over traditional bio‐synthesis approaches. This review summarizes the techniques developed for protein assembly, including native chemical ligation, Se‐mediated ligation, and a range of other ligation methods. A few synthetic examples, whereby synthetic proteins with desired modifications have been utilized for related biological research, are also included. We believe that chemical synthesis can provide alternative pathways to solve problems that have hitherto proved insurmountable by traditional biological approaches.

show abstract

Section: Native Chemical Ligation (Ncl)mentioning

confidence: 99%

Chemical Protein Synthesis by Native Chemical Ligation and Variations Thereof

et al. 2019

View full text Add to dashboard Cite

show abstract

“…The synthesis of a suitably protected (b-Se)-Asp building block began with electrophilic selenylation chemistry, analogous to the sulfenylation transformation we recently reported in the synthesis of thioamino acids. 4,13,14 Initially, our intention was to incorporate a 2,4,6-trimethoxybenzyl (Tmb)-protected selenol unit into the target amino acid. However, the instability of the Tmb-protected selenosulfonate precluded isolation.…”

Section: Synthesis Of B-selenoaspartate and G-selenoglutamate Buildinmentioning

confidence: 99%

“…With model diselenide dimer peptides 10 and 12 in hand, we next explored additivefree ligation reactions with a range of model selenoesters (13)(14)(15)(16)(17)(18)(19). Specifically, 10 or 12 and a given peptide selenoester (see Supplemental Experimental Procedures for selenoester synthesis and Figures S6-S12 for characterization data) were simply dissolved in 6 M Gdn,HCl and 0.1 M phosphate buffer at a final pH of 6.2-6.5 (with no additives or pH adjustment necessary).…”

Section: One-pot Additive-free Diselenide-selenoester Ligation-deselementioning

confidence: 99%

“…The rates of the additive-free diselenide-selenoester ligation reactions at both (b-Se)-Asp and (g-Se)-Glu were rapid, such that all reactions reached completion between 5 and 55 min (as judged by UPLC-MS analysis and by precipitation of diphenyldiselenide [DPDS], a visual prompt for completion of the reactions). Notably, ligations at selenoesters bearing C-terminal Ala (13), Ser (14), Phe (15), Tyr (16), Met (17), and Leu (18) were complete in 5-15 min, significantly faster than native chemical ligation at Cys and the homologous b-mercapto-Asp 4 and g-mercapto-Glu. 14 Furthermore, ligation with selenoester 19 with a sterically hindered C-terminal Val residue was complete in 55 min at Asp and 45 min at Glu, again significantly faster than the thiolate equivalents (b-mercapto-Asp 4 and g-mercapto-Glu 14 ; 16 hr).…”

Section: One-pot Additive-free Diselenide-selenoester Ligation-deselementioning

confidence: 99%

“…Native chemical ligation has revolutionized the field of protein science by facilitating access to native, modified, and designer biomolecules for interrogative studies on structure and/or function. 1,2 The need for a cysteine residue (the least abundant proteinogenic amino acid) on the N terminus of one of the reacting peptide fragments has motivated the development of b-, g-, and d-thiolated variants of other amino acids, [3][4][5][6][7][8][9][10][11][12][13][14] as well as thiol-containing auxiliaries that can be used as Cys surrogates in ligation chemistry. [15][16][17][18][19][20] After ligation reactions at these residues, the thiol auxiliary is desulfurized (usually by means of radical-based protocols 21 ) to yield native polypeptide products (Scheme 1A).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Accelerated Protein Synthesis via One-Pot Ligation-Deselenization Chemistry

Mitchell

Sayers

Kulkarni

et al. 2017

Chem

Self Cite

View full text Add to dashboard Cite

Here, we describe the development of a highly efficient one-pot ligationdeselenization technology at aspartate and glutamate that enables the synthesis of polypeptides and proteins on unprecedented timescales. The power of the methodology is showcased through the rapid assembly of three thrombininhibiting tick-derived proteins as well as the synthesis of the 21 kDa homodimeric selenoprotein K. This work lays the foundation for the facile synthesis of a range of bioactive polypeptides and proteins in the future. HIGHLIGHTSRapid one-pot ligationdeselenization at b-selenoaspartate and g-selenoglutamate Methodology enables chemical protein synthesis on unprecedented timescales Synthesis of Selenoprotein K through chemoselective deselenization of b-selenoaspartate Synthesis, purification, and quantification of thrombin inhibitory proteins in 3 hr Mitchell et al., Chem 2, 703-715 May 11, 2017 ª 2017 Elsevier Inc. http://dx. SUMMARYPeptide ligation chemistry has revolutionized protein science by facilitating access to synthetic proteins. Here, we describe the development of additive-free ligation-deselenization chemistry at b-selenoaspartate and g-selenoglutamate that enables the generation of native polypeptide products on unprecedented timescales. The deselenization step is chemoselective in the presence of unprotected selenocysteine, which is highlighted in the synthesis of selenoprotein K. The power of the methodology is also showcased through the synthesis of three tick-derived thrombin-inhibiting proteins, each of which were assembled, purified, and isolated for biological assays within a few hours. The methodology described here should serve as a powerful means of accessing synthetic proteins, including therapeutic leads, in the future.

show abstract

Amide‐Forming Ligation Reactions

2019

View full text Add to dashboard Cite

One of the long‐standing pursuits of synthetic organic chemists is the development of chemical methods for the synthesis of peptides and proteins as tools for understanding biological processes and providing therapeutic solutions to human diseases. The advent of chemoselective ligation reactions for the chemical synthesis of peptides and proteins has enabled synthetic chemists to realize this long‐held dream. In an amide‐forming ligation reaction, two uniquely placed functional groups within the peptide allow peptide or protein segments to be joined in a chemoselective manner with an amide bond. In this chapter, some of the early methods based on principles of the capture/rearrangement strategy for ligation of peptides are catalogued, followed by some of the most versatile and well‐established contemporary methods for the preparation of linear/cyclic peptides and proteins such as the native chemical ligation (NCL) and the α‐ketoacid–hydroxylamine (KAHA) ligation. The chapter concludes with some of the most promising new generation ligation methods such as the potassium acyltrifluoroborate–hydroxylamine (KAT) ligation. The tremendous progress in the past two decades in the development of several ligation methods that rely on a pair of unique functional groups is set to expand the horizons of fully functional proteins and multi‐protein assemblies that are purely synthetically prepared. Although contemporary ligation reactions do not match the speed and efficiency at which proteins are assembled in biological systems, the repertoire of chemoselective amide‐forming ligation methods has already enabled synthetic protein chemistry to surpass biology in terms of chemical and structural diversity.

show abstract

Thiazolidine-Protected β-Thiol Asparagine: Applications in One-Pot Ligation–Desulfurization Chemistry

Cited by 33 publications

References 40 publications

Chemical Protein Synthesis by Native Chemical Ligation and Variations Thereof

Chemical Protein Synthesis by Native Chemical Ligation and Variations Thereof

Accelerated Protein Synthesis via One-Pot Ligation-Deselenization Chemistry

Amide‐Forming Ligation Reactions

Contact Info

Product

Resources

About