Peptide Target Binder Development

Peptide molecules to specifically bind targets such as aptamer, avimer and kunitz domain have been intensively studied and developed as alternatives to antibodies. The peptides with high affinity to targets can be used as drugs or diagnostic agents, particularly where whole antibodies may be unsuitable. Given applicability and market potential of peptide molecules as drugs or diagnostic agents, a multitude of companies and laboratories are researching to seek peptide molecules with a novel structure.

Advantages of peptide target binder

• Small Molecular Weight
• Economic Production
• High Affinity to Target Molecules
• Unique structural scaffold
• Versatile Application

Applications of peptide target binder

By conjugation to a set of sixteen polypeptides, a small binding molecule can evolve into a polypeptide binder with increased affinity and selectivity.

• 2-oxo-1,2-dihydroquinoline-8-carboxylic acid (DQ) for development of high affinity binders targeting human C-reactive protein (CRP)

CRP is a well-known biomarker of inflammation in humans and binders recognizing it are therefore of large interest as medical diagnostics. Until now, phosphocholine (PCh) and derivatives are the only known small molecule binders for CRP, but they have low μM affinity and bind CRP in a Ca²⁺ dependent manner. The small molecule DQ was designed as a CRP binder that is structurally unrelated to PCh. Its polypeptide conjugate, 4-C25l22-DQ, was demonstrated as a strong, Ca²⁺ independent binder for CRP, and had an affinity approximately three orders of magnitude higher than DQ itself.

• Acetazolamide (AZM) for development of human carbonic anhydrase (HCA) II and IX

HCA IX is a protein that is interesting for diagnosis of cancer. AZM is a small molecule inhibitor of HCAs with a dissociation constant of 38 nM for HCA II and 3 nM for HCA IX. Interestingly, polypeptide conjugate 4-C10L17-AZM displayed stronger binding to both HCA II (KD 4 nM) and HCA IX (KD 90 pM). This result provided evidence that the binder concept can be applied also for small molecules which already have high affinity for their protein receptors.

• Peptidic macrocycles were developed as inhibitors of lysine specific demethylase1 (LSD1).

LSD1 is an enzyme that regulates the methylation of Lys 4 of histone 3 via a PPI-like interaction and which is of therapeutic interest in certain cancers. Based on the structures of two peptidic ligands bound to LSD1, we sequentially prepared truncated, mono-substituted and macrocyclic peptides in order to develop reversible inhibitors of LSD1. Some stapled cyclic peptides bound to LSD1 with 10-fold higher affinity than the corresponding linear parent peptide. Changing the staple into a lactam further improved the binding potency and the best lactams inhibited the enzymatic activity of LSD1 at low μM K_i values.

Strategies for discovering peptide binders

• Make chemical modifications to provide protease resistance and metabolic stability
• Obtain structural information to optimize target-binding modes
• Perform theoretical simulation to predict dynamic actions

In conclusion, it is important for the selection of peptide binders suitable for multiple purposes in biology, biotechnology, and medical science. Creative Peptides has extensively synthetic peptides binders which have potential as molecular target drugs comparable to that of monoclonal antibodies. It is the company of choice to manufacture your stapled peptide requirements, providing a confidential and efficient service at competitive prices. Every step of peptide synthesis is subject to Creative Peptides' stringent quality control. Typical delivery specifications include:

• HPLC chromatogram
• Mass spec analysis
• Synthesis report
• Certificate of Analyses

References

1. Huang, J., Ru, B., Li, S., Lin, H., & Guo, F. B. (2010). SAROTUP: scanner and reporter of target-unrelated peptides. BioMed Research International, 2010.
2. Sato, A. K., Viswanathan, M., Kent, R. B., & Wood, C. R. (2006). Therapeutic peptides: technological advances driving peptides into development. Current opinion in biotechnology, 17(6), 638-642.
3. Yang, J. (2017). Development of Peptide Binders: Applied to Human CRP, Carbonic Anhydrase (II, IX) and Lysine Demethylase 1 (Doctoral dissertation, Acta Universitatis Upsaliensis).