Article 18 · 10 min
A history of peptide chemistry, 1838 to the present
From Mulder naming protein to solid-phase synthesis, recombinant expression and the modern analytical era.
From proteins to peptide bonds
Modern peptide science emerged from nineteenth-century attempts to understand the nitrogen-rich substances isolated from biological tissues. In 1838, Gerardus Johannes Mulder used the term “protein” for what he believed to be a fundamental class of organic material. The molecular architecture was not yet known. By the turn of the twentieth century, Emil Fischer and contemporaries were systematically synthesising small peptide-like compounds and establishing that amino acids could be linked through amide bonds. Fischer popularised the term peptide and helped define the peptide bond as the structural connection underlying proteins.
The hormone era
The next major transition was from chemistry to biological function. Insulin was isolated and developed therapeutically in the early 1920s, demonstrating that a polypeptide hormone could carry a specific physiological signal. Over subsequent decades, oxytocin, vasopressin, substance P, ACTH fragments and many other endogenous peptides were isolated and structurally characterised. Vincent du Vigneaud's laboratory achieved the total synthesis of oxytocin in the 1950s, an important proof that a biologically active peptide could be assembled chemically and retain its function.
Merrifield and solid-phase synthesis
Peptide synthesis remained laborious until Robert Bruce Merrifield introduced solid-phase peptide synthesis in the 1960s. In this approach, the growing peptide chain is anchored to an insoluble resin. Reagents can be added in excess and washed away after each coupling step, allowing cycles of deprotection and amino-acid addition to be repeated efficiently. Automation followed, transforming peptide synthesis from a specialist multistep solution process into a scalable platform for producing defined sequences. Merrifield received the 1984 Nobel Prize in Chemistry for this work.
Expansion of synthetic chemistry
Advances in protecting groups, coupling reagents and resin chemistry increased the length and complexity of accessible sequences. Fmoc-based chemistry became widely used, while improved preparative HPLC enabled purification of synthetic products from deletion sequences and side products. Recombinant DNA technology meanwhile changed the production of larger peptide hormones and proteins. The field consequently divided into overlapping domains: chemical synthesis for many short and medium sequences, recombinant expression for larger biologics, and hybrid technologies such as native chemical ligation for complex peptides and proteins.
The analytical revolution
Analytical technology changed the meaning of peptide quality. Early identity depended heavily on elemental analysis, amino-acid composition, bioassay and painstaking chemical degradation. Modern reversed-phase HPLC provides high-resolution purity profiles, while electrospray and MALDI mass spectrometry can confirm molecular mass rapidly. High-resolution LC-MS/MS adds sequence-level evidence and can characterise modifications or impurities. Quality can therefore be documented batch by batch rather than inferred from a compound name or biological effect.
Mitochondrial and micropeptide discovery
Since the early 2000s, the field has expanded again through discovery of short open reading frames, mitochondrial-derived peptides and previously unrecognised endogenous micropeptides. Humanin, reported in the early 2000s, and MOTS-c, reported in 2015, are prominent examples. At the same time, peptide engineering has produced cyclised, lipidated, stapled and otherwise modified molecules designed to alter stability, receptor selectivity or distribution.
Evidence and funding context
The history also explains why evidence varies so widely. Some peptide medicines have undergone extensive clinical development; many research sequences remain supported mainly by cell or animal studies. Endogenous or near-endogenous sequences can be difficult to protect with broad composition-of-matter patents, which may reduce commercial incentives for large trials, although lack of funding should never be mistaken for evidence of efficacy or safety. The modern discipline is therefore defined by both technical power and evidentiary caution: peptides can be synthesised and characterised with extraordinary precision, but biological claims must still be judged by the quality of the experiments that support them.
References
- Mitchell AR. Bruce Merrifield and solid-phase peptide synthesis: a historical assessment. Peptide Science. 2008. DOI: 10.1002/bip.20925.