Bicyclic Peptide Drug Design: How Double-Ring Peptides Are Changing Medicine

What Are Bicyclic Peptides?

Bicyclic peptides are short chains of amino acids that form two connected rings.

Think of them like a figure eight or two loops joined together.

This double-ring shape gives them special properties that make them very useful for drug design.

Unlike straight-chain (linear) peptides, bicyclic peptides are more stable in the body and can bind to disease targets with great precision.

"Bicyclic peptides occupy a sweet spot in molecular weight and binding affinity that neither small molecules nor antibodies can easily access.", Sir Gregory Winter, Nobel Laureate in Chemistry, MRC Laboratory of Molecular Biology (2018)

Why Bicyclic Peptides Matter in Drug Design

Most drugs today fall into two groups: small molecules and large biologics (like antibodies).

Bicyclic peptides sit right in the middle, and that is what makes them so exciting.

They are big enough to grab onto flat, hard-to-target protein surfaces.

But they are small enough to potentially be taken as a pill someday.

The global peptide therapeutics market was valued at over $42 billion in 2023 and is expected to grow rapidly, according to Grand View Research (source).

Advantages of Bicyclic Peptides

Here are the main reasons why scientists are so interested in bicyclic peptides for drug design.

• Better stability. The two rings protect the peptide from being broken down by enzymes in the body.
• Stronger binding. The rigid shape helps the peptide lock onto its target like a key in a lock.
• Larger contact area. Two rings can touch more of the target surface than a single ring or straight chain.
• Smaller than antibodies. This means they can reach places in the body that big antibody drugs cannot.
• Easier to make. Compared to antibodies, bicyclic peptides are simpler and cheaper to produce.

Bicycle Therapeutics' lead compound BT1718 can bind its target with nanomolar affinity despite being roughly 50 times smaller than a typical antibody.

How Scientists Make Bicyclic Peptides

There are several ways to create bicyclic peptides in the lab.

Each method has its own strengths.

Chemical Scaffold Approach

The most popular method uses a small chemical molecule as a "scaffold" or connector.

The scaffold links to three reactive spots on the peptide chain (usually cysteine amino acids) to form two loops.

One common scaffold is TBMB (1,3,5-tris(bromomethyl)benzene).

This approach was pioneered by Professor Christian Heinis at EPFL in Switzerland.

Disulfide Bond Method

This older method uses natural disulfide bonds between cysteine residues to form the rings.

It is simpler but gives less control over which cysteines pair up.

Enzymatic Cyclization

Some enzymes can naturally create ring structures in peptides.

Scientists have learned to use these enzymes to make bicyclic peptides with very specific shapes.

Click Chemistry

Click chemistry reactions can also be used to connect parts of the peptide chain into rings.

This method is very reliable and works under mild conditions.

The Bicycle Therapeutics Platform

One company leading the way in bicyclic peptide drug design is Bicycle Therapeutics.

They developed a technology platform called Bicycle, which creates synthetic bicyclic peptides using the chemical scaffold approach.

Their lead drug candidate, BT8009, targets Nectin-4, a protein found on many cancer cells.

How the Platform Works

1. A large library of random peptide sequences is created.
2. The peptides are cyclized using the TBMB scaffold.
3. Phage display is used to screen billions of candidates.
4. The best binders are selected and optimized.

This process can find high-quality drug candidates in just a few months.

Key Applications of Bicyclic Peptides

Bicyclic peptides are being studied for many different diseases.

Cancer Treatment

Bicyclic peptides can be attached to toxic drugs to create peptide-drug conjugates (PDCs).

These PDCs deliver the toxic drug directly to cancer cells, sparing healthy tissue.

This is similar to how antibody-drug conjugates work, but bicyclic peptides can penetrate tumors more deeply.

Inflammatory Diseases

Some bicyclic peptides can block the signals that cause inflammation.

This makes them potential treatments for conditions like rheumatoid arthritis and inflammatory bowel disease.

Infectious Diseases

Bicyclic peptides have been designed to block viral proteins, stopping viruses from entering human cells.

This approach is being explored for diseases like COVID-19 and influenza.

Cardiovascular Disease

Researchers are developing bicyclic peptides that can prevent dangerous blood clots without the bleeding risks of current blood-thinning drugs.

For teams working in these areas, having access to specialized peptide research talent makes a major difference in project timelines.

If your team is expanding into bicyclic peptide programs, prioritize hiring chemists with hands-on phage display and TBMB scaffold experience, as these skills are scarce and critical to accelerating your discovery pipeline.

Comparing Bicyclic Peptides to Other Drug Types

Feature	Small Molecules	Bicyclic Peptides	Antibodies
Molecular weight	Less than 500 Da	1,500 to 3,000 Da	150,000 Da
Target types	Enzyme pockets	Flat protein surfaces	Flat protein surfaces
Oral availability	Usually yes	Sometimes	No
Tumor penetration	Good	Very good	Poor
Manufacturing cost	Low	Moderate	High
Half-life in body	Hours	Hours to days	Weeks

Challenges in Bicyclic Peptide Drug Design

While bicyclic peptides offer many advantages, there are still challenges to overcome.

Oral Delivery

Most bicyclic peptides still need to be injected because they are broken down in the stomach.

Scientists are working on chemical modifications to make them survive the digestive system.

Short Half-Life

Bicyclic peptides are cleared from the body faster than antibodies.

Researchers solve this by attaching them to albumin-binding groups or PEG molecules, which slow down their removal.

Manufacturing Scale-Up

Making bicyclic peptides in large quantities for clinical use requires careful process development.

The cyclization step must be very precise to get the right ring structure.

Understanding the latest peptide macrocycle synthesis methods helps teams tackle these manufacturing challenges.

Design Strategies for Better Bicyclic Peptides

Scientists use several strategies to improve bicyclic peptide drug candidates.

Sequence Optimization

After finding a lead peptide, researchers make small changes to the amino acid sequence to improve binding and stability.

They often use a method called alanine scanning, where each amino acid is replaced one at a time with alanine to see which positions are most important.

Unnatural Amino Acids

Adding amino acids not found in nature can make bicyclic peptides more resistant to breakdown by enzymes.

D-amino acids (mirror images of natural L-amino acids) are commonly used for this purpose.

Scaffold Variation

Trying different chemical scaffolds can change the shape and size of the loops.

This can improve how well the peptide fits its target.

Multimerization

Connecting two or more bicyclic peptides together can increase their binding strength.

This is especially useful when the target protein has multiple binding sites.

"Bicyclic peptides represent a sweet spot in drug design. They combine the target selectivity of biologics with the tissue penetration and manufacturing simplicity of small molecules." This view is widely shared among medicinal chemists working in the peptide drug space.

Looking Ahead

Several bicyclic peptide candidates are now in clinical trials for cancer and other diseases.

As synthesis methods improve and new scaffold chemistries are discovered, bicyclic peptides are on track to become a significant class of therapeutic drugs.

AI-driven design, high-throughput screening, and advanced manufacturing will continue to speed up the discovery of new bicyclic peptide medicines.

Bicyclic peptides combine the target selectivity of biologics with the tissue penetration of small molecules, making them one of the most promising new drug modalities for peptide-focused organizations to invest in now.

Frequently Asked Questions

What is a bicyclic peptide?

A bicyclic peptide is a short chain of amino acids that forms two connected ring structures. The two rings give the peptide a rigid, stable shape that helps it bind tightly to protein targets. This makes bicyclic peptides useful as drug candidates.

How are bicyclic peptides different from cyclic peptides?

Cyclic peptides have one ring, while bicyclic peptides have two connected rings. The extra ring gives bicyclic peptides more structural rigidity and a larger surface area for binding targets. This often results in stronger and more selective binding.

Can bicyclic peptides be taken as pills?

Most bicyclic peptides currently need to be injected. However, researchers are working on chemical modifications that would allow some bicyclic peptides to survive the stomach and be absorbed through the gut. Some early results in this area are promising.

What diseases can bicyclic peptides treat?

Bicyclic peptides are being developed for cancer, inflammatory diseases, cardiovascular conditions, and infectious diseases. The most advanced clinical programs focus on using bicyclic peptide-drug conjugates to deliver chemotherapy drugs directly to cancer cells.

How long does it take to develop a bicyclic peptide drug?

From initial screening to a clinical candidate, bicyclic peptide drug development typically takes 2 to 4 years. This is often faster than antibody drug development because bicyclic peptides are easier to synthesize and optimize. Clinical trials then add several more years.

Who invented bicyclic peptides?

The modern approach to bicyclic peptide drug design was largely developed by Professor Christian Heinis and colleagues. They introduced the chemical scaffold method using TBMB to create constrained bicyclic peptides from linear precursors displayed on phages.