Peptide linkers are crucial components in bioconjugation, protein engineering, and drug development. They are short peptide sequences and serve as molecular bridges that connect different functional units within a biomolecule or between biomolecules. Their design and choice can significantly influence the stability, functionality, and efficacy of the final products, such as fusion proteins and antibody-drug conjugates (ADCs).
Peptide linkers have been widely used biopharmaceutical research.
- Provide flexibility and freedom of movement between connected domains or components, which is essential for maintaining the functional activity of proteins or conjugates. For instance, in fusion proteins, peptide linkers can help the two protein domains fold correctly and maintain their functional conformations.
- Provide flexibility and freedom of movement between connected domains or components, which is essential for maintaining the functional activity of proteins or conjugates.
- Act as spacers to prevent steric hindrance or interference between functional groups or domains. In ADCs, linkers prevent the cytotoxic drug from affecting the antibody’s binding ability or interacting with unintended targets.
- Influence solubility, stability, and bioavailability of the conjugated molecule. Properly designed linkers can enhance the solubility and reduce aggregation of the protein or conjugate.
- In some applications, linkers are designed to be cleavable under specific conditions (e.g., enzymatic cleavage or pH changes) to release active drug or imaging agents at the target sites.
Peptide linkers can be classified as flexible linkers, non-flexible linkers, cleavable linkers and non-cleavable linkers.
- Flexible Linkers are made from amino acids such as glycine, serine, or alanine, providing flexibility and allowing for free rotation, such as (Gly₄Ser)₂ and (Gly₃Ser)₂.
- Rigid Linkers include secondary structures such as alpha-helices or beta-sheets that provide rigidity and maintain a specific orientation between connected domains.
- Cleavable Linkers are designed to be cleaved by specific enzymes or under certain conditions. They are extremely useful for controlled release of drugs or payloads. Peptides with protease cleavage sites like Val-Cit, Val-Ala, Val-Gly, Ala-Ala-Asn, and Gly-Phe-Leu-Gly are widely used in ADC research.
- Non-Cleavable Linkers provide stable and permanent connections without the intention of releasing the linked components.
- PEG-peptide linkers combine the advantages of polyethylene glycol (PEG) with peptide sequences to create versatile and functional linkers for various applications in biotechnology and pharmaceutical development. PEG-peptide linkers are used to connect cytotoxic drugs to antibodies. The PEG component enhances solubility, while the peptide linker provides a specific and controlled connection.
Peptide linkers are essential tools in modern biochemistry and drug development, offering flexible and tailored solutions for connecting functional components in a wide range of applications. Their design involves balancing flexibility, stability, and functionality to optimize the performance of the final conjugate or fusion protein. From antibody-drug conjugates to protein engineering and molecular imaging, peptide linkers play a pivotal role in advancing scientific research and therapeutic development.
Ref:
Liming Gong, Heming Zhao, Yanhong Liu, Hao Wu, Chao Liu, Shuangyan Chang, Liqing Chen, Mingji Jin, Qiming Wang, Zhonggao Gao, Wei Huang, Research advances in peptide‒drug conjugates, Acta Pharmaceutica Sinica B, Volume 13, Issue 9, 2023, Pages 3659-3677.
AxisPharm has a large collection of peptide linkers, PEG peptide linkers, and PEGylated peptide synthesis reagents in stock. Custom syntheses of peptide PEG are available upon request.
