The present review offers an overview of nonclassical (e.g., with no pre- or in situ activation of a carboxylic acid partner) approaches for the construction of amide bonds. The review aims to comprehensively discuss relevant work, which was mainly done in the field in the last 20 years. Organization of the data follows a subdivision according to substrate classes: catalytic direct formation of amides from carboxylic and amines (section 2); the use of carboxylic acid surrogates (section 3); and the use of amine surrogates (section 4). The ligation strategies (NCL, Staudinger, KAHA, KATs, etc.) that could involve both carboxylic acid and amine surrogates are treated separately in section 5.

Nonclassical Routes for Amide Bond Formation

The modification of proteins with non-protein entities is important for a wealth of applications, and methods for chemically modifying proteins attract considerable attention. Generally, modification is desired at a single site to maintain homogeneity and to minimise loss of function. Though protein modification can be achieved by targeting some natural amino acid side chains, this often leads to ill-defined and randomly modified proteins. Amongst the natural amino acids, cysteine combines advantageous properties contributing to its suitability for site-selective modification, including a unique nucleophilicity, and a low natural abundance--both allowing chemo- and regioselectivity. Native cysteine residues can be targeted, or Cys can be introduced at a desired site in a protein by means of reliable genetic engineering techniques. This review on chemical protein modification through cysteine should appeal to those interested in modifying proteins for a range of applications.

Chemical Protein Modification through Cysteine

S-to-N acyl transfer is a high-yielding chemoselective process for amide bond formation It is widely utilized by chemists for synthetic applications, including peptide and protein synthesis, chemical modification of proteins, protein-protein ligation and the development of probes and molecular machines Recent advances in our understanding of S-to-N acyl transfer processes in biology and innovations in methodology for thioester formation and desulfurization, together with an extension of the size of cyclic transition states, have expanded the boundaries of this process well beyond peptide ligation As the field develops, this chemistry will play a central role in our molecular understanding of Biology The conversion of thioesters to amides via acyl transfer has become one of the most important synthetic techniques for the chemical synthesis and modification of proteins This review discusses this S-to-N acyl transfer process, and highlights some of the key applications across chemistry and biology

/pdf/exploring-chemoselective-s-to-n-acyl-transfer-reactions-in-5ety4pkqt1.pdf

Exploring chemoselective S-to-N acyl transfer reactions in synthesis and chemical biology.

Solid phase peptide synthesis (SPPS) provides the possibility to chemically synthesize peptides and proteins. Applying the method on hydrophilic structures is usually without major drawbacks but faces extreme complications when it comes to "difficult sequences." These includes the vitally important, ubiquitously present and structurally demanding membrane proteins and their functional parts, such as ion channels, G-protein receptors, and other pore-forming structures. Standard synthetic and ligation protocols are not enough for a successful synthesis of these challenging sequences. In this review we highlight, summarize and evaluate the possibilities for synthetic production of "difficult sequences" by SPPS, native chemical ligation (NCL) and follow-up protocols.

/pdf/challenges-and-perspectives-in-chemical-synthesis-of-highly-3a5y85tc2f.pdf

Challenges and Perspectives in Chemical Synthesis of Highly Hydrophobic Peptides.

The pharmaceutical market has largely been dominated by small molecule drugs; however, larger biomolecules have recently become important contenders. Of these biomolecules, protein and peptide therapeutics are proving useful due to their often improved pharmacokinetic properties. In many circumstances, functionalisation of the protein or peptide therapeutics results in performance enhancement, and various methodologies are applied. In addition, introducing unnatural amino acids for structural reinforcement via chemical modification is also common. These strategies are discussed in this review.

Bioconjugation – using selective chemistry to enhance the properties of proteins and peptides as therapeutics and carriers

Ionic liquids as reaction media for oxidative folding and native chemical ligation of cysteine-containing peptides

This review focuses on chemical ligation methods for the preparation of oligopeptides and proteins. Chemical ligation is a practical and convenient methodology in peptide and protein synthesis. Longer peptides and proteins can be obtained with high yield in aqueous buffer solutions by coupling unprotected peptide segments even without activation by enzymes or further chemical agents. Several methods and protocols were developed in the past. The potential of the most important approaches of the thioester- and imine-ligation techniques is demonstrated by a broad spectrum of applications. In addition, special features and protocols such as the template-directed ligation, ligation with novel additives or solvent media, microwave-assisted ligation, and the achievements obtained with those are also highlighted herein.

Synthetic strategies for polypeptides and proteins by chemical ligation

Ionic liquid 1-ethyl-3-methylimidazolium acetate: an attractive solvent for native chemical ligation of peptides

Synthetic Strategies for Polypeptides and Proteins by Chemical Ligation

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Ionic liquids as reaction media for oxidative folding and native chemical ligation of cysteine-containing peptides

Synthetic strategies for polypeptides and proteins by chemical ligation

Ionic liquid 1-ethyl-3-methylimidazolium acetate: an attractive solvent for native chemical ligation of peptides

Synthetic Strategies for Polypeptides and Proteins by Chemical Ligation