How are peptides made in the lab?
Chemical Synthesis of Peptides
Peptides can be created in the laboratory through a well-established technique known as chemical synthesis, which allows scientists to construct specific amino acid sequences with a high degree of precision. The most widely used approach is solid-phase peptide synthesis (SPPS), which involves anchoring the first amino acid to a solid resin, then sequentially adding protected amino acids to form the desired chain.
To ensure that each amino acid reacts only at the appropriate site, protecting groups are used. These chemical groups temporarily block reactive side chains or termini, preventing unintended interactions during the synthesis process. Once the full peptide sequence has been assembled, these protecting groups are removed through controlled reactions, and the peptide is cleaved from the resin. The crude peptide is then purified, often via high-performance liquid chromatography (HPLC), to remove impurities and ensure that the final product meets structural and functional specifications.
Why Chemically Synthesize Peptides?
Chemical peptide synthesis is not just about creating copies of natural peptides—it is a versatile tool that enables the engineering of peptides with enhanced biological functions or novel properties. Key objectives include:
Enhancing desired biological activity: Many peptides influence multiple physiological pathways. Chemical synthesis allows researchers to refine the structure to amplify a specific therapeutic effect while minimizing others.
Improving stability and bioavailability: Naturally occurring peptides often degrade quickly in the body, especially in the digestive tract. Chemical modifications can make them more resistant to enzymatic breakdown and improve their pharmacokinetic profile, enabling longer-lasting effects or even oral administration.
Reducing side effects: By fine-tuning the peptide structure, researchers can increase target specificity, minimizing off-target interactions that could cause adverse effects.
Elucidating structure-activity relationships (SAR): Chemical synthesis enables the production of peptide analogs with single amino acid changes, allowing scientists to systematically study how structure influences function.
Creating novel, non-natural peptides: Synthesis can produce peptides that do not exist in nature, including peptidomimetics, cyclic peptides, or peptides incorporating non-proteinogenic amino acids, opening new frontiers in drug discovery.
Advantages of Chemical Peptide Synthesis
Compared to recombinant DNA or enzymatic methods, chemical synthesis offers several compelling benefits:
Scalability: Synthesis can be carried out from milligram-scale for research to multi-gram or kilogram-scale for industrial production, supporting both early-phase development and commercialization.
Efficiency for short sequences: Chemical methods are especially effective for synthesizing peptides up to 50 amino acids, where biological expression systems may be cumbersome or inefficient.
Freedom from biological contaminants: Synthetic peptides are inherently BSE/TSE-free (no risk of prion contamination), ensuring safety, especially for therapeutic use.
Customization and flexibility: Researchers can easily alter amino acid sequences, introduce chemical tags, or incorporate unnatural residues to create peptides with novel or enhanced functions.
Facilitates functional modification: Chemical synthesis supports the introduction of specific modifications such as PEGylation, lipidation, or cyclization, enabling tailored solutions for drug delivery, targeting, and stability.
Chemical peptide synthesis remains a cornerstone of modern pharmaceutical research, enabling the precise design, optimization, and production of therapeutic peptides for use in fields such as endocrinology, oncology, neurology, and regenerative medicine.
