Chemical Synthesis of Peptides and Proteins

Chemical synthesis of peptides and proteins encompasses a suite of methodologies that enable the precise assembly of amino acid sequences for applications in therapeutics, diagnostics and fundamental biology. Central to this field is solid-phase peptide synthesis (SPPS), in which an anchored growing chain undergoes iterative deprotection and coupling cycles to yield peptides of defined length and composition. Advances in protecting-group chemistry and reagents have extended the reach of SPPS to challenging sequences and enabled the incorporation of post-synthetic modifications. Complementary solution-phase strategies, including native chemical ligation and related acyl-transfer techniques, allow for the convergent assembly of longer polypeptides and full-length proteins. Innovations in green chemistry and waste-minimisation address the environmental footprint of large-scale manufacture, while novel ligation handles and chemoselective transformations facilitate site-specific labelling and the synthesis of modified proteins, such as ubiquitin conjugates or diselenide-bridged analogues. Together, these developments have broadened the scope of chemical synthesis, providing access to complex biomolecules for drug discovery, chemical biology and structural studies.

Research from Nature Portfolio

Recent studies have transformed the efficiency and versatility of peptide synthesis. A new SPPS protocol eliminates all solvent-intensive wash steps by harnessing controlled headspace evaporation, reducing base consumption by up to 85% and cutting waste by more than 90% without compromising product quality. Alternative protecting-group strategies have been introduced to tackle aspartimide formation by installing cyanosulfurylide masks on carboxylates; these groups confer enhanced solubility and stability, then undergo rapid aqueous deprotection via selective carbon–carbon bond cleavage. In parallel, palladium-mediated on-demand cysteine-deprotection tools now permit orthogonal removal of multiple thiol-protecting groups in aqueous medium, enabling the synthesis of highly modified proteins and activity-based probes with precise control over modification sites.

Chemical Synthesis of Peptides and Proteins publication trend

The graph below shows the total number of articles in chemical synthesis of peptides and proteins across all publications each year (not limited to Nature Index journals).

Technical terms

Solid-phase peptide synthesis (SPPS): A method in which peptides are assembled stepwise on an insoluble resin support, enabling repeated coupling and deprotection cycles.

Fmoc: 9-Fluorenylmethoxycarbonyl, a base-labile protecting group commonly used to mask the amino terminus during SPPS.

Native chemical ligation (NCL): A chemoselective ligation technique that joins unprotected peptide segments via transthioesterification and subsequent S-to-N acyl transfer.

Protecting group: A chemical moiety temporarily attached to reactive functional groups to prevent side reactions during multi-step synthesis.

Aspartimide formation: A side reaction in peptide synthesis where an aspartate residue cyclises to form a succinimide, leading to sequence heterogeneity and yield loss.

References

1. Total wash elimination for solid phase peptide synthesis. Nature Communications (2023).
2. Advances in Fmoc solid‐phase peptide synthesis. Journal of Peptide Science (2016).
3. Sustainability Challenges in Peptide Synthesis and Purification: From R&D to Production. The Journal of Organic Chemistry (2019).
4. The greening of peptide synthesis. Green Chemistry (2017).
5. Chemical Synthesis of Ubiquitin, Ubiquitin‐Based Probes, and Diubiquitin. Angewandte Chemie International Edition (2010).
6. Palladium prompted on-demand cysteine chemistry for the synthesis of challenging and uniquely modified proteins. Nature Communications (2018).
7. Exploring chemoselective S-to-N acyl transfer reactions in synthesis and chemical biology. Nature Communications (2017).
8. Cysteine protecting groups: applications in peptide and protein science. Chemical Society Reviews (2021).
9. Prevention of aspartimide formation during peptide synthesis using cyanosulfurylides as carboxylic acid-protecting groups. Nature Communications (2020).
10. Challenges and Perspectives in Chemical Synthesis of Highly Hydrophobic Peptides. Frontiers in Bioengineering and Biotechnology (2020).