Early Discoveries and Key Figures
The field of peptide research has a rich history, dating back to the early 20th century when scientists began to unravel the complexities of proteins and peptides. Early breakthroughs in peptide chemistry laid the foundation for modern biological and medicinal research. One of the earliest and most significant discoveries was the identification of insulin as a peptide hormone, which revolutionized the treatment of diabetes. In 1921, Frederick Banting and Charles Best isolated insulin from the pancreas, demonstrating its role in regulating blood glucose levels. This landmark discovery led to the development of insulin as a therapeutic agent, saving countless lives.1
In the 1950s and 1960s, Robert Merrifield a member of our organization, developed Solid-Phase Peptide Synthesis, SPPS, which transformed the field of peptide chemistry by enabling the efficient and automated synthesis of peptides.2 Merrifield’s work earned him the Nobel Prize in Chemistry in 1984 and remains a cornerstone of peptide research. His method allowed scientists to produce peptides of defined sequences with high precision, facilitating research in areas such as enzyme inhibitors, vaccines, and therapeutic peptides.
Vincent du Vigneaud, also a member of the American Peptide Society, was another pioneer in peptide science. In 1955, he became the first to successfully synthesize a peptide hormone oxytocin, which plays a crucial role in childbirth and social bonding. Du Vigneaud’s work provided an early glimpse into the power of synthetic peptides, showcasing their potential in both basic research and medicine.3
Landmark Discoveries in Peptide Therapeutics
The development of peptide-based therapeutics has been a driving force in modern pharmacology. One of the most well-known therapeutic peptides is insulin, which continues to be a life-saving treatment for individuals with diabetes. Advances in insulin analogs, such as lispro and glargine, have improved its pharmacokinetics, allowing for more precise control of blood sugar levels in diabetic patients.
Another landmark discovery in peptide therapeutics was the development of angiotensin-converting enzyme, ACE, inhibitors in the 1970s. These peptides prevent the conversion of angiotensin I to angiotensin II, a peptide that causes vasoconstriction. Captopril, the first ACE inhibitor, revolutionized the treatment of hypertension and heart failure, providing an entirely new class of drugs.4
Peptide vaccines have also made a significant impact in the field of immunotherapy. Peptides derived from pathogens or cancer cells can be used to elicit immune responses in the body, providing a targeted approach to both prevention and treatment. The development of peptide-based vaccines against hepatitis B and human papillomavirus, HPV has been a major public health success, reducing the incidence of these infections and their associated cancers.5
Peptide Length and Nomenclature: Oligopeptides, Polypeptides, and Proteins
Peptides are categorized based on their length and structure, with varying terms used to describe them depending on the number of amino acid residues they contain. The term oligopeptide typically refers to short chains of amino acids, usually fewer than 10 residues. These small peptides often serve regulatory or signaling functions in biological systems. Examples of oligopeptides include bradykinin, which mediates inflammation, and glutathione, which acts as an antioxidant in cellular processes.6
A polypeptide is a longer chain of amino acids, typically containing between 10 and 50 residues. Polypeptides form the building blocks of proteins but may also function independently as hormones, enzymes, or antimicrobial agents. Antimicrobial peptides, AMPs, such as defensins and cathelicidins, are examples of polypeptides that play a critical role in the innate immune response by disrupting microbial membranes.
When a polypeptide chain exceeds 50 amino acids, it is usually referred to as a protein. Proteins may consist of one or more polypeptide chains folded into complex three-dimensional structures, allowing them to perform a wide range of biological functions. Examples include enzymes, antibodies, and structural proteins such as collagen and keratin. While all proteins are polypeptides, not all polypeptides function as fully formed proteins, highlighting the importance of folding and structural organization in biological activity.
Post-Translational Modifications, PTMs
Once synthesized, peptides and proteins often undergo post-translational modifications, PTMs, which expand their functional diversity and regulate their activity, stability, and interactions. PTMs involve the covalent addition or removal of functional groups or the cleavage of specific peptide bonds. One of the most common PTMs is phosphorylation, in which a phosphate group is added to serine, threonine, or tyrosine residues by kinases. This modification plays a crucial role in cell signaling pathways, particularly in the regulation of enzyme activity and protein-protein interactions.7
Glycosylation is another important PTM, involving the addition of sugar moieties to asparagine, serine, or threonine residues. This modification is essential for protein folding, stability, and immune recognition. Many membrane-bound and secreted proteins, such as antibodies and hormones, are glycosylated to ensure proper function. The glycosylation of antibodies, for example, influences their ability to bind to immune receptors and trigger an immune response.
Other PTMs include acetylation, ubiquitination, and disulfide bond formation. Acetylation of lysine residues can affect chromatin structure and gene expression by modifying histone proteins. Ubiquitination tags proteins for degradation by the proteasome, a critical process for maintaining cellular homeostasis. Disulfide bonds, formed between cysteine residues, are essential for stabilizing the three-dimensional structure of many extracellular proteins, such as insulin and immunoglobulins.
Conclusion
The history of peptide research is marked by significant discoveries that have shaped modern medicine and biochemistry. From early work on peptide hormones to the development of therapeutic peptides and vaccines, the field has continued to evolve, offering new insights into the fundamental mechanisms of biology. Key concepts such as peptide length, nomenclature, and post-translational modifications further underscore the complexity and versatility of peptides in biological systems.
Citations and Links
1. Banting, Frederick, and Charles Best. “The Discovery of Insulin.” Canadian Medical Association Journal, vol. 121, no. 2, 1922, pp. 13-20.
2. Merrifield, Robert B. “Solid Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide.” Journal of the American Chemical Society, vol. 85, no. 14, 1963, pp. 2149-2154. doi:10.1021/ja00897a025.
3. Vigneaud, Vincent du. “The Synthesis of Oxytocin.” Journal of Biological Chemistry, vol. 205, no. 1, 1955, pp. 949-960.
4. Ondetti, Miguel A., et al. “Captopril: A Specific Inhibitor of Angiotensin-Converting Enzyme in Man.” Science, vol. 196, no. 4288, 1977, pp. 441-444. doi:10.1126/science.301613.
5. Harper, Diane M., et al. “Efficacy of a Bivalent L1 Virus-Like Particle Vaccine in Prevention of Infection with Human Papillomavirus Types 16 and 18 in Young Women.” The Lancet, vol. 364, no. 9447, 2004, pp. 1757-1765. doi:10.1016/S0140-6736(04)17398-4.
6. Irvine, W. J., et al. “Bradykinin in Inflammation.” British Journal of Pharmacology, vol. 38, no. 3, 1970, pp. 235-244.
7. Hunter, Tony. “Protein Phosphorylation: The Story of a Paradigm.” Journal of Cell Biology, vol. 168, no. 2, 2005, pp. 203-213. doi:10.1083/jcb.200409073.