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 molecules with sub-nanomolar affinity against diverse targets and target classes (including: enzymes, proteases, receptors, GPCRs, surface ligands and secreted proteins). Indeed, many target classes of high biological and commercial interest previously thought intractable to a selective small molecule approach, such as the metalloproteases, serine proteases and interleukins have been selectively drugged using Bicycles. In contrast to antibodies, Bicycles also generally exhibit cross-species activity, which allows a more precise extrapolation from efficacy and toxicology experiments. Bicycles present a large surface area for binding (500–1000 Å2) allowing them to modulate protein-protein interactions. However, in contrast to antibodies, they have a low molecular weight (1.5–2 kDa), providing rapid and deep tissue penetration, and are likely to avoid the immunogenicity that is often problematic in antibody development. Bicycles have been defined as small molecules by the regulatory authorities, are chemically synthesised and highly soluble, 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.


Bicycles combine the beneficial attributes of three other drug classes into a single modality to deliver therapies with unique properties


The video above models the molecular dynamics of an 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 amino acid side chains being more frequently presented to the target in the correct orientation for binding. This constraint provides Bicycles their antibody-like affinity and specificity.


The cornerstone to Bicycle Therapeutics’ value proposition is its proprietary technology that enables the systematic cyclisation of peptides on the surface of phage with variable loop sizes to generate large, diverse phage display libraries comprising more than 10 15 unique Bicycles. The platform combines the power of evolution driven biological selection with the antibody-like affinity and selectivity conferred by the constraint of a chemical scaffold. Screening can be conducted against either isolated proteins or with whole cells expressing the target of interest.


Bicycles can generate vast chemical libraries that are screened via phage display following cyclisation of the initially linear peptides. Additional diversity and differential properties can also be derived from variations in scaffolding agent and in Bicycle loop size and format.

Bicycle Therapeutics has conducted over 80 screens and has successfully identified high potency Bicycles in 80% of these against a variety of targets many of which have been intractable to a small molecule approach, including cytokines, chemokines, enzymes, proteases and a diverse collection of cell surface receptors such as GPCRs, extracellular tethered enzymes and receptor tyrosine kinases. These screens have been performed on a diverse array of different scaffolding agents, which we have shown to deliver additional desirable properties to the Bicycle, including improved physicochemical properties and differential levels of structural constraint.

BICYCLE® screening process


The Bicycle screening process consists of multiple iterative rounds of phage selection combined with identification of the Bicycle using sequencing and a parallel functional assay to determine its binding and affinity.

A hugely diverse set of cyclised peptides is initially generated using phage display and subsequently incubated as phage-bound Bicycles with soluble target proteins or alternatively transfected cells can be substituted to screen integral membrane protein. Phage that bind to the target are recovered on a matrix and identification of the encoded Bicycle is via sequencing and, unique to this platform, a parallel functional assay is performed to determine binding affinity to inform structure relationship activities. The screening process, optimized over the course of many target campaigns, is highly efficient, rapid and progresses over multiple rounds of phage selections. During these selections, a vast and diverse chemical space is sampled from numerous phage libraries that are prioritised to represent a wide variety of binding motifs and pharmacophores. Subsequently, the chemical space is narrowed using evolved-selection to identify the most promising Bicycles by sequentially affinity maturing and re-randomizing the Bicycle libraries until high affinity high selectivity molecules are identified. The use of a functional binding assay is a key activity that differentiates our platform from other cyclic peptide companies, which use only mono-cyclized peptides and select these by simple abundance in the recovered target-binding fraction. By combining functional activity with the sequence information that encodes the Bicycle, informative structure activity relationships (SAR) are generated at every stage of our screening process. This allows rational redesign of bespoke target-specific libraries and their use in iterative rounds of evolution driven phage selection. In this stepwise iterative fashion we select, expand, and qualify chemical space, allowing us to efficiently identify high affinity binders and a core pharmacophore to the designated target.

Helix forming Bicycle with its peptide backbone shown as a ribbon and its core scaffold shown as sticks, bound to the ligand binding domain of a receptor tyrosine kinase, shown as a surface hydrophobicity plot.

Helix forming Bicycle with its peptide backbone shown as a ribbon and its core scaffold shown as sticks, bound to the ligand binding domain of a receptor tyrosine kinase, shown as a surface hydrophobicity plot.