ArticleNature protocols2016
Protein chemical synthesis by α-ketoacid-hydroxylamine ligation.
Article in Nature protocols, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 52 citations in OpenAlex.
- Cyclic Hydroxylamines for Native Residue-Forming Peptide Ligations: Synthesis of Ubiquitin and Tirzepatide.Journal of the American Chemical Society · 2025Article
- Advances in the chemical synthesis of human proteoforms.Science China. Life sciences · 2025Review
- In vitro and in vivo evaluation of chemically synthesized, receptor-biased interleukin-4 and photocaged variants.Science advances · 2025Article
- A biocatalytic platform for asymmetric alkylation of α-keto acids by mining and engineering of methyltransferases.Nature communications · 2023Article
- Biocompatible Lysine Protecting Groups for the Chemoenzymatic Synthesis of K48/K63 Heterotypic and Branched Ubiquitin Chains.ACS central science · 2023Article
- Synthesis of full-length homodimer αD-VxXXB that targets human α7 nicotinic acetylcholine receptors.RSC medicinal chemistry · 2022Article
- Chemical approaches for investigating site-specific protein S-fatty acylation.Current opinion in chemical biology · 2021Review
- Diselenide-selenoester ligation for chemical protein synthesis.Nature protocols · 2019Article
- Amide-forming chemical ligation viaProceedings of the National Academy of Sciences of the United States of America · 2018Article
- Advancing the Frontiers of Chemical Protein Synthesis-The 7Cell chemical biology · 2018Article
- Total chemical synthesis of histones and their analogs, assisted by native chemical ligation and palladium complexes.Nature protocols · 2017Article
- Chemical Synthesis of the Highly Hydrophobic Antiviral Membrane-Associated Protein IFITM3 and Modified Variants.Angewandte Chemie (Weinheim an der Bergstrasse, Germany) · 2017Article
- Chemical Synthesis of the Highly Hydrophobic Antiviral Membrane-Associated Protein IFITM3 and Modified Variants.Angewandte Chemie (International ed. in English) · 2017Article
- Aligator: A computational tool for optimizing total chemical synthesis of large proteins.Bioorganic & medicinal chemistry · 2017Review
- Chemical synthesis of a homoserine-mutant of the antibacterial, head-to-tail cyclized protein AS-48 by α-ketoacid-hydroxylamine (KAHA) ligation.Chemical science · 2017Article
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Authors and funding
3 authors at 1 institution in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Total chemical synthesis of proteins allows researchers to custom design proteins without the complex molecular biology that is required to insert non-natural amino acids or the biocontamination that arises from methods relying on overexpression in cells. We describe a detailed procedure for the chemical synthesis of proteins with the α-ketoacid-hydroxylamine (KAHA ligation), using (S)-5-oxaproline (Opr) as a key building block. This protocol comprises two main parts: (i) the synthesis of peptide fragments by standard fluorenylmethoxycarbonyl (Fmoc) chemistry and (ii) the KAHA ligation between fragments containing Opr and a C-terminal peptide α-ketoacid. This procedure provides an alternative to native chemical ligation (NCL) that could be valuable for the synthesis of proteins, particularly targets that do not contain cysteine residues. The ligation conditions-acidic DMSO/H2O or N-methyl-2-pyrrolidinone (NMP)/H2O-are ideally suited for solubilizing peptide segments, including many hydrophobic examples. The utility and efficiency of the protocol is demonstrated by the total chemical synthesis of the mature betatrophin (also called ANGPTL8), a 177-residue protein that contains no cysteine residues. With this protocol, the total synthesis of the betatrophin protein has been achieved in around 35 working days on a multimilligram scale.
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