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Review
. 2005:34:91-118.
doi: 10.1146/annurev.biophys.34.040204.144700.

Chemical synthesis of proteins

Bradley L Nilsson  1 , Matthew B Soellner, Ronald T Raines
Affiliations
Review

Chemical synthesis of proteins

Bradley L Nilsson et al. Annu Rev Biophys Biomol Struct. 2005.

Abstract

Proteins have become accessible targets for chemical synthesis. The basic strategy is to use native chemical ligation, Staudinger ligation, or other orthogonal chemical reactions to couple synthetic peptides. The ligation reactions are compatible with a variety of solvents and proceed in solution or on a solid support. Chemical synthesis enables a level of control on protein composition that greatly exceeds that attainable with ribosome-mediated biosynthesis. Accordingly, the chemical synthesis of proteins is providing previously unattainable insight into the structure and function of proteins.

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Figures

Figure 1
Figure 1
Solid-phase peptide synthesis.
Figure 2
Figure 2
A general strategy for peptide ligation.
Figure 3
Figure 3
Prior thiol capture.
Figure 4
Figure 4
Native chemical ligation.
Figure 5
Figure 5
Expressed protein ligation.
Figure 6
Figure 6
Prosthetic modules installed into RNase A by expressed protein ligation (6, 7).
Figure 7
Figure 7
Ligation at an incipient alanine residue.
Figure 8
Figure 8
Ligation at an incipient methionine residue.
Figure 9
Figure 9
Acyl-initiated capture.
Figure 10
Figure 10
Frequency of occurrence of amino acid residues in the primary structures of 1021 unrelated proteins (89). The most common residues at ligation junctions in synthetic proteins are cysteine (as in native chemical ligation) and glycine (see below).
Figure 11
Figure 11
Auxiliary-mediated peptide ligation.
Figure 12
Figure 12
Native chemical ligation with Nα-ethanethiol and Nα-oxyethanethiol auxiliaries.
Figure 13
Figure 13
Nα-2-Mercaptobenzylamine-assisted chemical ligations.
Figure 14
Figure 14
Nα-(1-Phenyl-2-mercaptoethyl)-assisted chemical ligation.
Figure 15
Figure 15
Precedents for the Staudinger ligation of peptides. Top: Vilarrasa and coworkers (20); Bottom: Bertozzi and coworkers (123).
Figure 16
Figure 16
Staudinger ligation of peptides mediated by a phosphinothiol.
Figure 17
Figure 17
Comparison of functional group interconversions during native chemical ligation and phosphinothiol-mediated Staudinger ligation. Dissimilar groups are boxed.
Figure 18
Figure 18
Phosphinothiols used in the Staudinger ligation of peptides.
Figure 19
Figure 19
Phosphinophenol used in the Staudinger ligation of peptides at nonglycyl residues.
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