Alfa Chemistry is an expert in the field of drug discovery and has established an advanced DNA-encoded libraries (DELs) technology platform dedicated to building and synthesizing a large number of novel, diverse, drug-like compound libraries.
Our world-class laboratories and scientists can support your unique synthetic needs and help you apply macrocyclic peptide DELs to enable affinity screening against targeted proteins for hit discovery.
Introduction to Macrocyclic Peptides
Peptide drugs offer high specificity and potency akin to biologics and they can effectively penetrate cells to intracellular drug targets depending on their composition and molecular properties. However, linear peptides derived from natural amino acids are subjected to proteolysis, leading to rapid degradation in vivo.
In order to overcome these limitations, cyclic peptides (polypeptide chains taking on a cyclic ring structure) have attracted attention as a promising alternative. Macrocyclic peptides are cyclic peptides with a ring size of at least 12 atoms in size and span multiple amino acid residues, and they can bridge the molecular worlds of small and macromolecules. Due to their excellent proteolytic resistance and structural stability, macrocyclic peptides have become a new focus of therapeutic drugs and research [1, 2].
Fig. 1 Published macrocyclic peptides DELs [1].
Advantages of Macrocyclic Peptides
Macrocyclic peptides have gained traction in clinical disease treatment due to their numerous advantages over linear peptides. These advantages are listed below [2].
- Enhanced Stability and Binding Affinity: Cyclization of peptides reduces their conformational freedom, leading to improved metabolic stability and higher binding affinity and specificity to target proteins.
- Increased Surface Area: Macrocyclic peptides, being larger than traditional small molecule drugs, can interact with target proteins over a larger surface area. This enables them to exhibit exceptional protein affinity and specificity.
- Structural Diversity: Macrocyclic peptides offer extensive structural diversity. By utilizing the 20 protein-derived amino acids, hundreds of different cyclic peptides can be generated. Furthermore, this diversity can be expanded by incorporating nonprotein amino acids.
- Retained Small Molecule Properties: In contrast to proteins, macrocyclic peptides maintain some characteristics of small molecules, including stability, reduced risk of immune response, synthesizability, and lower production costs.
Our Capabilities
Leveraging the advanced DELs technology platform, Alfa Chemistry offers professional macrocyclic peptide DELs synthesis services for screening diverse target proteins and identifying macrocyclic peptide compounds with high affinity and potency.
- Our synthesis strategies for macrocyclic peptides DELs encompass DNA template-based synthesis (DTS) and DNA-recorded synthesis, with the latter being the predominant method in both academia and industry.
- Alfa Chemistry employs natural and unnatural amino acids in DNA-recorded synthesis, utilizing split & pool procedures in combinatorial chemistry. This approach facilitates the creation of DELs of macrocyclic peptides that cover different chemical spaces.
- Alfa Chemistry possesses the expertise to address the synthesis challenges in the synthesis of macrocyclic peptides DELs, which are mainly around the cyclization reaction of the peptide.
- In peptide synthesis, macrocyclization stands out as a critical and demanding step, requiring reaction compatibility with DNA. Alfa Chemistry's arsenal of synthetic tools encompasses a range of DNA-compatible cyclization strategies for peptide macrocyclization.
- During the DELs synthesis of macrocyclic peptides, cyclization occurs at the final stage. However, as all library compounds are pooled throughout the synthesis process and cannot be reacted uniformly and individually purified, leading monitoring cyclization reactions poses challenges. Alfa Chemistry has the ability to quantify the reaction, monitoring the progress of the cyclization reaction through analysis such as changes of molecular weight.
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References
- Plais, L.; Scheuermann, J. Macrocyclic DNA-encoded chemical libraries: a historical perspective. RSC Chem. Biol. 2022, 3: 7-17.
- Zhu, Z.; et al. Design and application of a DNA-encoded macrocyclic peptide library. ACS Chem. Biol. 2018, 13(1): 53–59.