Bicycles® are highly constrained bicyclic peptides, typically between 9 and 15 amino acids in size. The structural constraint, delivered using a variety of proprietary molecular scaffolds, results in molecules with antibody-like target specificity and high affinity as demonstrated by the company’s generation of multiple sub-nanomolar binders against diverse targets and target classes (including: enzymes, proteases, receptors, surface ligands and secreted proteins). Bicycles® present a large surface area for binding (500–1000 Å2) allowing them to modulate protein-protein interactions. However, in contrast to antibodies, Bicycles® are small (1.5–2 kDa), providing rapid and deep tissue penetration, show cross-species reactivity and are likely to avoid the immunogenicity that is often problematic in antibody development. Bicycles® are chemically synthesised, highly soluble and have been confirmed as small molecules by the regulatory authorities, providing manufacturing and formulation flexibility. Finally, as Bicycles® are peptidic, they have “tuneable” pharmacokinetics and are cleared by the kidney thereby avoiding gastrointestinal and liver exposure with the risk of associated toxicity.
The video below models the molecular dynamics of the same amino acid sequence as a linear peptide (left), as a monocycle (centre) and as a Bicycle® (right). The greater constraint of the Bicycle® results in the three side chains being more frequently in the correct orientation for binding to the target. This gives Bicycles® their antibody-like affinity and specificity.
BICYCLE® TECHNOLOGY: A NEW CLASS OF THERAPEUTICS COMBINING SEVERAL ADVANTAGES
Phage display of large, diverse bicyclic peptides
- Allows rapid identification of diverse, high selective and high affinity Bicycles®
Small Size (1.5–2kDa)
- Potential for extensive tissue distribution
Desirable characteristics for lead development
- Tuneable pharmacokinetics
- Predictable elimination
- Amenable to a broad range of formulations
- Aqueous solubility and stability
Simple chemical synthesis
- Ease of manufacture
- Bicycle® payloads
- Bispecific Bicycles®