Bicyclic Peptides Synthesis

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Creative Peptides is a leading peptides synthesis service vendor which has the expertise and ability in providing bicyclic peptide synthesis service for customers worldwide. Creative Peptides' sophisticated equipments, advanced technologies and highly experienced staffs are available to provide you with the most affordable, high-quality bicyclic peptides synthesis service to ensure your satisfaction in a timely and professional manner.

What are bicyclic peptides?

Bicyclic peptides are a type of peptide that contain two distinct peptide loops, typically connected by chemical crosslinks. They have a diverse range of biological activities and are of significant interest in drug discovery and development due to their high stability, selective binding, and ability to modulate protein-protein interactions. These characteristics make them an attractive middle ground between small molecule drugs and larger protein therapeutics.

Advantages of bicyclic peptides

The clinical potential of peptides with limited chemical structure has attracted more and more attention. Limiting the chain flexibility of peptides may not only enhance the binding strength and selectivity between them and the target, but also optimize their pharmacokinetic characteristics and enhance their drug-like properties.

Compared with the more common monocyclic peptides, polycyclic peptides have gradually become a more emerging field. Bicyclic peptides have many advantages over linear and monocyclic peptides. Their size, structure, function and increased conformational rigidity improve their proteolytic stability and binding performance in blood circulation and provide better tissue penetration. The binding characteristics of bicyclic peptides are somewhat similar to those of antibodies, and its structure makes it particularly suitable for interfering with protein-protein interaction (PPI). Both rings may bind to different regions of potential targets, or even to two different targets. Bicyclic peptides may have some advantages of monoclonal antibodies (high target specificity and affinity) and small molecules (stability and good tissue permeability), so they can have different therapeutic and diagnostic applications.

Fig.1 Applications of bicyclic peptides. (Rhodes, C. A., 2017)

Structural types and synthesis of bicyclic peptides

What methods can be used to synthesize bicyclic peptides?

Bicyclic peptides are a very important class of structures in biochemistry. With the continuous development of researchers, there have been rich methods to manage the construction of bicyclic structures. Traditional methods include amide or ester condensation reaction, while recent methods include natural chemical connection, olefin/alkyne translocation and palladium-catalyzed C-C bond formation. Reymond and his team developed a specific method in 2015. They created cyclic peptides by crosslinking lysine and glutamic acid residues, and obtained bicyclic peptides by reacting cysteine residues with N-terminal chloroacetyl. In addition, the method of aspartic acid ligation as a fairly mature method also has great potential in synthesizing bicyclic structures. Among the methods for the construction of bicyclic peptides, the methods utilizing thioether bonds and disulfide bonds are particularly prominent. Cyclization via sulfhydryl groups is common in the peptides from natural origin, and this is a common strategy for artificial synthesis of bicyclic peptides. Thanks to the development of organic chemistry methodology, increasing thiol-based bicyclic peptide synthesis methods have been reported in recent years.

In 2018, Perrin used the intramolecular Savige-Fontana reaction to complete the total synthesis of death-cap mushroom toxin α-amanitin.

Fig. 2 Synthesis of death-cap mushroom toxin α-amanitin. (Feng, D., 2023)

Structural types of bicyclic peptides

Based on the bicyclic structure, bicyclic peptides can be roughly divided into two parts, the main chain of amino acids and the connecting chain. According to the position and type of the connecting chain, they can be further divided into four types.

• The first type of bicyclic peptide is the simplest motif for which a further linkage connecting two side chains (R₁ of type I, Fig. 3A) was formed inside of a head-to-tail cyclized macrocyclic peptide (type I). This type of bicyclic peptide can be successfully constructed by a two-step cyclization reaction. Native chemical ligation (NCL) was first reported as an independent method in 1994.
• In the second type of bicyclic peptide (type II), there is a partial overlap between the two loops. When the linker is an amide bond, the structure is often similar in form to some of the first type of bicyclic peptide.
• The third motif is a linear backbone linking two separate macrocyclic peptides (see the red in type III). In the synthesis of the first and third types of bicyclic peptides, if the connection site is improperly designed or inappropriate protective groups are used, the second type may also appear as impurities in the reaction system. Meanwhile, there are also some methods with good selectivity can take into account the synthesis of the second type and third type of bicyclic peptides. In 2021, Li and cooperators reported a synthetic strategy for constructing diverse peptide via chemoselective peptide ligation.
• The fourth type of bicyclic peptide involves small molecule compounds that are used as a backbone to connect the peptide chain to form a handcuff-shaped structure (type IV). More conveniently, there are a variety of choices for small molecules (Fig. 3B), such as tris-(bromomethyl) benzene and 3,5-bis(mercaptomethyl)benzoic acid (BMB). Since the construction of the fourth type is relatively fast, convenient, and more suitable for the rapid synthesis of a large quantity, it has been widely used in the construction of bicyclic peptide libraries.

Fig. 3 Various types of bicyclic peptide structures. (A) Four common types of bicyclic peptides. (B) General forms of link chains. (Feng, D., 2023)

Applications of bicyclic peptides

Bicyclic peptides have found applications in various scientific fields such as medicine, pharmaceutical research, and materials science.

Drug discovery: Bicyclic peptides can be designed to bind to specific protein targets with high affinity and specificity. Because of this property, they are potential candidates for drug discovery, specifically for diseases that involve protein-protein interactions.

Therapeutics: Bicyclic peptides can serve as a scaffold for the development of novel therapeutic agents. For instance, certain bicyclic peptides have anticancer, antiviral, antibacterial, and immunomodulatory activity.

Diagnostic tools: Bicyclic peptides can also be used in diagnostics as they can detect disease-related biomarkers. They can be engineered to bind to certain molecules within the body, making them useful in imaging studies or as part of diagnostic tests.

Material science: Bicyclic peptides have been used to create new materials, like hydrogels. When designed to self-assemble, the peptides can form a structure that holds water, creating a gel-like material that has potential uses in biomedical applications, such as drug delivery or tissue engineering.

Probes in biological research: Due to their stability and high binding affinity, bicyclic peptides can be used as probes to study biological processes and structures.

Antimicrobial Agents: Some bicyclic peptides have been found to demonstrate potent antimicrobial activities against various Gram-positive and Gram-negative bacteria, including drug-resistant strains.

Our services

Custom synthesis: We synthesize bicyclic peptides as per your specifications. Our team of experienced scientists are dedicated to produce high-quality, purifiable compounds with unparalleled attention to detail. The following is our classic synthesis case.

Fig. 4 A bicyclic peptide synthesized by Creative Peptides.

• The deprotection, OMs protection and alkylation of hydroxyl groups were successfully completed on solid phase.
• Successfully obtained the product with HPLC purity over 96%.

Library synthesis: We can generate a diverse array of bicyclic peptides to help facilitate the exploration of the vast biological space. This broadens the possibility of finding effective drug targets and therapeutics.

Peptide drug discovery: Utilizing the distinct advantages of bicyclic peptides, like high stability and target selectivity, we help you develop more potent, reliable, and safe drug candidates.

Biological assessment: Beyond synthesis, we offer services to evaluate the biological activity of the synthesized peptides. We employ various assays in cell cultures and animal models, testing the effects on the target, toxicity, and efficacy.

Purification and characterization: We offer high quality purification and characterization services, ensuring that your peptides are of optimal purity and precisely identified and quantified.

Large scale synthesis: We can also upscale the synthesis process, ensuring that your supply of bicyclic peptides meets your demand.

Consultation services: Our experts are available to consult on project direction, provide alternative solutions, and troubleshoot problems related to the synthesis and use of bicyclic peptides.

As the world's largest producer of synthetic peptides, Creative Peptides is able to provide you the bicyclic peptides service with advanced platform, quick turnaround, and uncompromising quality results. Creative Peptides is a reliable partner that can work with you to accelerate the speed to achieve your research goals. If you have any peptide synthesis requirement in mind, please do not hesitate to contact us. We are looking forward to working together with your attractive projects.

FAQ

1. What are bicyclic peptides?

Bicyclic peptides are a class of peptides that contain two ring structures. They have noteworthy potential as therapeutic agents due to their unique features, including high stability, specificity, and the ability to bind to targets that are typically difficult for traditional small molecules.

2. Can you design and synthesize personalized bicyclic peptides for me?

Yes, we can. Our team of experienced scientists can design bicyclic peptides based on your provided sequence or specific needs. You just have to let us know what you need, and we will handle the rest.

3. How long does it take to synthesis a custom bicyclic peptide?

The total time for bicyclic peptide synthesis depends on the complexity and length of the sequence you need. Generally, the process could take from few weeks to several months. We assure you that we prioritize quality and accuracy over speed.

4. What guarantees do you provide regarding the quality of the peptides?

We adhere to strict quality control procedures to ensure that all synthesized peptides are of the highest quality. We do HPLC purification and MS analysis to guarantee the purity and accuracy of all peptides.

5. Do you provide worldwide shipping?

Yes, we do. Our service extends globally, and we make sure all products are packed appropriately to maintain their integrity until they reach you no matter where you are located.

References

1. Ahangarzadeh, S., et al. Bicyclic peptides: types, synthesis and applications. Drug Discovery Today. 2019, 24(6): 1311-1319.
2. Rhodes, C. A., et al. Bicyclic peptides as next-generation therapeutics. Chemistry-A European Journal. 2017, 23(52): 12690-12703.
3. Feng, D., et al. Current development of bicyclic peptides. Chinese Chemical Letters. 2023, 34(6): 108026.