Peptide lead optimization

Increasing peptide drug potency and improving pharmacokinetic properties through lead optimization of linear and CLIPS-constrained peptides


Schematic visualization of the lead optimization proces. Based on an initial lead (left), full replacement analysis using both natural & non-natural amino acids identifies those amino acids in the lead sequence that are essential to binding, as well as the amino acids that contribute to affinity improvement. Iterative synthesis & screening cycles with affinity-optimized sequences result in an optimized candidate peptide.

Lead optimization is a critical step in the design of novel peptide-based drugs. Pepscan’s scientists build on over 25 years of experience. Our highly skilled project teams combine chemistry and biology expertise and are well-equipped to bring a peptide lead drug candidate to the next level.

Peptide leads can be optimized in three ways:

1. through amino acid replacement analysis,
2. by constraining peptides using our in-house CLIPS technology, or
3. by improving the peptide length/size.

By combining these modifications in iterative screening rounds, we have demonstrated that we can improve the affinity of peptide-based lead drug candidates up to 1000 times.

We have developed a diverse library of enhanced CLIPS molecules, which after incorporation can lead to improved peptide conformation as well as better pharmacokinetic properties. This addition directly affects the potency of lead drug candidates, for example through:

  • improved specificity,
  • complex stability, and
  • decreased elimination/clearance.

Custom-made libraries to optimize your therapeutic peptide lead

At Pepscan, we have been designing, synthesizing and applying peptide array technology for many years. You can tap into this knowledge by using our design assistance. We provide recommendations to create the most efficient and economical library design and help you to compute lists of peptide library sequences. By combining pre-defined modifications in iterative screening rounds, peptides with a higher affinity can be identified.

Upon request, we produce peptide libraries with different structural modifications, such as N-terminal acetylation, biotinylation, Ser/Thr-phosphorylation, N-methylation, or labeling with fluorescent dyes.

Key benefits of Pepscan’s lead optimization

  • Detailed insights into the critical amino acids of the core epitope of a lead peptide
  • Possibility to further improve binding affinity by introducing a large variety of non-natural amino acids
  • Additional insights through mutational analysis and alanine scanning (ala scan)
  • Development of an enhanced molecule by constraining it (e.g. using CLIPS) for better pharmacokinetic properties, such as improved specificity, complex stability and decreased elimination/clearance, which directly affects the potency of a lead drug candidate
  • Possibility to include various in-house functional assays to determine proteolytic and/or enzymatic stability profiles of a lead peptide candidate

Pepscan’s team of experts

Peter Timmerman, PhD – Chief Scientific Officer – Peter Timmerman joined Pepscan in 2001 and is responsible for scientific developments at Pepscan. He is inventor of the CLIPS technology and also holds a chair as Professor (by special appointment) in Protein Mimetic Chemistry at the University of Amsterdam. He is co-author of over 80 scientific papers and co-inventor on >10 patents.

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