Broaden the Horizon: Find New Chemical Entities by Introducing BiBridged™ Cyclization Topologies

Peptide-Based Drugs

Macrocyclic drugs can be divided into peptide and non-peptide macrocycles. Peptide macrocycles merge biological characteristics with chemical ones, making them ideal for discovering leads for seemingly undruggable target proteins. One of their key advantages is the ability to harness biological tools – such as mRNA and phage display – to rapidly screen high-diversity libraries and identify interesting leads.

Peptide macrocycles are also easier to optimize compared to natural and synthetic macrocycles, which enables screening of cyclic peptide libraries of various ring sizes, utilizing the readily available diversity offered by natural and non-natural amino acid variants. Through cyclization technologies and medicinal chemical strategies, limitations of metabolic stability and poor half-life can be overcome.

Identifying Small-Sized Peptides for Therapeutic Targets with BiBridged™ Cyclization Technology

Structural diversity as well as compound library size are THE key factors for successful screening campaigns. Even with large combinatorial libraries, it may still be a challenge to achieve sufficient ligand diversity. This challenge can be solved by using two instead of one chemical linkage to cyclize peptides, as used in the BiBridged™ peptide topology. This allows for rapid access to billions of different macrocyclic ligands within the libraries. Additionally, the BiBridged™ peptide topology offers unique possibilities for enhancing the permeability and oral bioavailability of peptides.

These so-called BiBridged™ peptides are constrained by two chemical linkers instead of only one, which drastically improves resistance to proteolytic degradation – and boosts the sampling space to identify target binders. These peptides are easy to synthesize, screen, and decode. The Christian Heinis group (EPFL Lausanne) applied this double-constrained cyclization strategy to identify small-sized peptides for therapeutic targets like plasma kallikrein¹, coagulation factor XIa, or Interleukin-23². This also opens the possibility to identify therapeutic peptides suitable for oral administration.

The properties of these double-constrained peptidic macrocycles can be further modulated by incorporating non-natural amino acids or non-peptidic components to improve their potency, selectivity, or physicochemical properties. In addition, the various half-life extension tools developed for protein and peptide drugs can be easily adapted for peptide macrocycles to tailor the pharmacokinetic behavior as defined by the target product profile.

In 2020, Sangram Kale – inventor of the double-constrained BiBridged™ technology, joined the Pepscan team, which enabled Pepscan to extend its Peptide Discovery platform with BiBridged™ macrocycles. This method is applied in combination with a validated subset of the CLIPS™ scaffolds used in monocyclic CLIPS™ peptide libraries. Because of the higher level of constraint, the BiBridged™ lead peptides have much higher affinities than single CLIPS™ peptides, next to also being much more stable against enzymatic degradation.

Interested in learning how we can support your specific peptide case? Feel free to reach out to Peter Timmerman, Chief Scientific Officer at Pepscan.

1. Kale SS et al., “Cyclization of peptides with two chemical bridges affords large scaffold diversities”, Nat. Chem. 2018, 10, 715-23.
2. Kong X-D et al., “De novo development of proteolytically resistant therapeutic peptides for oral administration”, Nat. Biomed. Eng. 2020, 4, 560-3.
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