Regioselective α-Peptide Bond Formation Through the Oxidation of Amino Thioacids

Abstract

Biological systems, including ribosomes and enzymes, produce peptides with an extraordinary high speed and accuracy. On the other hand, a rational and regioselective α-peptide bond formation, without involving protecting groups, is difficult to achieve in chemical synthesis. In this study, α-amino thioacids were utilized for the generation of polypeptides without using any protecting groups. We found that an α-amino thioacid could oxidatively form a diaminoacyl-disulfide moiety and undergo a subsequent intramolecular S- to N-acyl transfer to form an α-peptide bond. Even the thioacid form of lysine, which has a free ε-amino group, generated a regioselective α-peptide bond. The oxidation of amino thioacids generated the oligomers of amino acids. Interestingly, this oligomerization reaction proceeded even in the presence of iron ore, a prebiotic element, thus suggesting a plausible prebiotic peptide bond forming reaction.

Selective incorporation of proteinaceous over nonproteinaceous cationic amino acids in model prebiotic oligomerization reactions

“…It was previously suggested that the selection of Lys over shorter analogs (Orn, Dab, and Dpr) is related to the ability of Lys to form superior ion-pairing interactions with negatively charged amino acids in helical structures (46); however, that model was undermined by the observation that replacement of Lys with Dab can increase the stability of protein−protein interactions in other contexts (47). An alternative mechanism that achieves regioselective α-amidation of Lys involving oxidation of amino thioacids has recently been put forth (48). The robust cyclization of Orn and Dab under dry-down conditions may have served as a selective force to exclude them from the repertoire of coded amino acids.…”

Glycoprotein Semisynthesis by Chemical Insertion of Glycosyl Asparagine Using a Bifunctional Thioacid-Mediated Strategy

“…To set up alternative synthesis methods, we studied several key reactions based on amino thioacids (Figure B, C). Thioacids were originally used as acylation functionalities for condensation and ligation reactions with azide, aziridine, thiocarbamate, isocyanide, and sulfonamide. − Because we were interested in the potent nucleophilicity and low p K a (∼3) value of thioacids compared with carboxylic acids, our group also studied chemoselective thioacid polymerization reactions with nonprotected amino thioacids ( I ) via oxidation processes in acidic solutions (Figure B) . The thioacid group is oxidized to form a diacyl disulfide bond ( II ), which is a potent acyl donor.…”

Selective amide bond formation in redox-active coacervate protocells

“…Ferricyanide has been described as a prebiotically abundant oxidizing agent, 33 and has been used to activate amino thioacids by oxidation to facilitate the formation of an amide bond upon reaction with nucleophilic aminonitriles and amino acids. [6][7][8][9]34 However, the oxidative aminoacylation of thioacids is usually performed with high reactant and ferricyanide concentrations (sometimes close to 100 mM), which could have been difficult to reach everywhere on Early Earth. Therefore, the highly concentrated ferricyanide coacervate droplets could be interesting model compartments for prebiotic amide bond formation (Fig.…”

“…They are considered interesting alternatives to biological thioesters for prebiotic peptide ligation, and can be ligated into peptide with the aid of an oxidizing catalyst, such as ferricyanide. [7][8][9][10] However, high concentrations of reactants and catalysts are typically required for these oxidative peptide ligations, which may not have been easy to reach. Recent work has demonstrated that some micro-compartments and protocell systems could compartmentalize (bio)chemical reactions, and act as catalytic microreactors or reaction localization centers with potential for prebiotic peptide ligation.…”