The What, Why and How of Cyclic Peptides

What is a Cyclic Peptide?

Peptides possess distinctive characteristics that render them highly attractive as therapeutic agents. Cyclic peptides are a group of peptide subtype containing one or more cyclic structures produced through end-to-end, cephalic or side-chain-to-side-chain cyclization reactions. Cyclic peptides are mostly composed of 5-30 amino acids, with a molecular weight between 500-3000 Da. Cyclic peptides continue to be one of the most alluring prospects in modern drug discovery endeavors due to their relatively small size, capacity to selectively and strongly interact with their targets, adaptability and relatively straightforward synthesis.

Advantages of Cyclic Peptides

Compared to their linear counterparts, cyclic peptides have several advantages. When used as drugs or targeting agents, linear peptides often suffer from inherent instability and are highly susceptible to intracellular proteolysis. In contrast, cyclization induces intramolecular hydrogen bonding within the ring structure, reducing the molecule’s external hydrogen bonding capacity and thereby lowering its overall polarity compared to the acyclic precursor. As a result, the membrane permeability of the compound increases, making it more efficient at passing through cellular membranes to reach intracellular targets. Furthermore, cyclization leads to the formation of two β-turn local secondary structures, which further reduces the polar surface area and generally enhances cell permeability. Cyclic peptides adopt more rigid conformations, thereby increasing their binding affinity and specificity to targets. In addition, the reduced conformational flexibility diminishes the likelihood of the molecules fitting into protease catalytic sites, leading to improved proteolytic resistance. The formation of larger interaction surfaces in cyclic peptides allows for more effective intervention in protein-protein interactions, further enhancing the efficacy of the peptide chain as a therapeutic agent.

Applications of Cyclic Peptides

Cyclization has bolstered the spectrum of potency, specificity and safety of the peptide chain, endowing cyclic peptides with the potential to be promising drug candidates. Up to 2022, of the more than 60 peptide drugs approved by the FDA and EMA, more than two thirds are in the cyclic form. One of the most famous cyclic peptide drugs is Cyclosporine (also known as Ciclosporin). It is an immunosuppressive agent that is widely used to prevent organ transplant rejection and treat various autoimmune diseases, such as rheumatoid arthritis and psoriasis. Cyclosporine is derived from a cyclic peptide produced by the fungus Tolypocladium inflatum. It works by suppressing the immune system’s response, particularly the activation of T-cells, which are involved in immune reactions and can attack transplanted organs. By inhibiting this immune response, Cyclosporine helps in preventing the rejection of transplanted organs.

Using cyclic peptides as targeting ligands for the targeted delivery of drugs has emerged as a promising strategy in the field of drug delivery. The above-mentioned advantages of cyclic peptides make them ideal candidates for enhancing drug specificity and efficacy. Through the precise recognition of specific cellular receptors, cyclic peptides hold the potential for more personalized and potent therapies. An illustrative example of this targeted drug delivery approach is the use of cyclic RGD (Arg-Gly-Asp) peptides (i.e., cRGD) as cyclic targeting ligands; cRGD peptides have a high affinity for integrin receptors, which are overexpressed on the surface of various cancer cells. By conjugating chemotherapy to an RGD cyclic peptide, the drug can be delivered directly to the cancer cells, specifically targeting the tumor site while minimizing damage to healthy tissues. This targeted delivery approach not only enhances the therapeutic effect of the drug but also reduces systemic toxicity, leading to improved patient outcomes and potentially fewer side effects.

Discovery of Cyclic Peptide Candidates

Among FDA-approved cyclic peptide drugs, a significant proportion derives from natural compounds or endogenous active substances found in the body. An example is ziconotide, sourced from the venom of the Conus magus snail. Functioning as a potent and selective blocker of N-type calcium channels, ziconotide effectively manages severe chronic pain.

Advancements in modern technologies for designing (e.g., structure-guided design and de novo in silico screening) and library screening of cyclic peptides (e.g., phage display and mRNA display) have led to an exponential progression in the discovery of bioactive cyclic peptides, specifically tailored to bind targets with exceptional affinity and specificity.

High-Throughput Library Screening Technology

Zilucoplan, designated as an orphan drug by the FDA, stands as a remarkable exception as it was developed through mRNA display technology. This innovative drug acts as a complement C5 inhibitor, countering the production of C5a induced by LPS in human blood and thereby utilized in the treatment of myasthenia gravis.

While the number of drugs discovered through high-throughput library screening and brought to market remains limited, numerous outstanding lead compounds have advanced to the late clinical stages, holding great promise for future drug developments. On May 10, 2023, Bayer and Bicycle Therapeutics jointly announced a series of strategic collaboration agreements to discover, develop, manufacture, and commercialize Bicycle radioconjugates for multiple agreed upon oncology targets. Under the agreement, Bayer will make a $45 million upfront payment, along with potential milestone payments of up to $1.7 billion, making the total amount up to $1.745 billion.

KS-V Peptide strives to advance novel cyclic peptide discovery that leads to drugs and targeting ligands for therapeutic applications, by our featured peptide discovery platform KPDS™. KS-V Peptide provides:

• High quality target protein generation for screening to secure success from the source.
• Our featured in-house libraries: 1 linear, 4 monocyclic, 3 bicyclic, and 2 tricyclic peptide libraries with more than 1010 peptides from 7-30 amino acids for high throughput phage display.
• Various peptide modification and optimization technologies to improve peptide stability and binding affinity/specificity.
• Featured structural biology analysis and AI-assisted design to identify most efficient peptide sequence.

Learn more about KS-V Peptide, our research focus and our service options, by visiting our website.