1. Introduction

Protein–protein interactions (PPIs) are essential to cellular processes such as signal transduction, apoptosis, immune regulation, and transcriptional control. The modulation of PPIs represents a high-value strategy in drug discovery. However, the development of effective PPI inhibitors has been historically limited by the inherent challenges of targeting large, flat, and dynamic protein interfaces often considered "undruggable" by conventional small molecules [1]. In contrast to biologics, such as monoclonal antibodies, provide high affinity and specificity, but their therapeutic utility is restricted by their limited tissue penetration, oral bioavailability, and inability to reach intracellular targets [2].
Cyclic peptides have gained considerable interest as a novel class of therapeutic agents, capable of bridging the gap between small molecules and biologics [3]. Their macrocyclic structure imparts conformational rigidity, enhancing binding affinity and selectivity while improving resistance to enzymatic degradation. Importantly, they can be engineered to possess favorable pharmacokinetic properties, including improved cell permeability and stability.
This blog aims to review the structure, modifications, and therapeutic applications of cyclic peptides, drawing from key developments in recent research and highlighting their increasing relevance as a modality in therapeutic innovation.

2. Cyclic Peptides: Structure, Properties, and Modifications

2.1 Structural Overview and Physicochemical Properties

Cyclic peptides differ fundamentally from linear peptides in both structure and function. While linear peptides consist of amino acids connected in a straight chain with free N- and C-termini, cyclic peptides feature a covalently closed ring structure formed through linkages such as head-to-tail cyclization, side-chain-to-side-chain bonds, disulfide bridges, or backbone-side-chain connections [4]. This structural constraint imparts greater conformational rigidity to cyclic peptides, which significantly enhances their stability and biological performance. Approximately 20–40% of known protein–protein interfaces are considered accessible to macrocyclic inhibitors, significantly expanding the druggable proteome [5].

2.1.1 Types of Cyclization

• The primary types of cyclization include:
• Head-to-tail cyclization: The most common form, involving the formation of an amide bond between the N-terminal amine and the C-terminal carboxyl group
• Side-chain-to-side-chain cyclization: This strategy utilizes covalent linkages between the functional groups of side chains, commonly involving amide bonds (e.g., between Lys and Asp/Glu residues), disulfide bridges (between cysteine residues forming cystine), or chemically introduced cross-linkers that yield stapled peptides. This method allows for topological diversity without constraining the peptide backbone termini
• Backbone-to-side-chain and side-chain-to-tail cyclization: These mixed-linkage strategies involve covalent bonding between the peptide backbone and side-chain residues (e.g., Glu side chain with backbone amine) or between a side chain and the C-terminus. These forms of cyclization further expand the conformational space and can be used to fine-tune bioactivity and target specificity
• Enzymatically cyclized peptides: Utilize site-specific ligation enzymes such as sortase A, butelase-1, or inteins to catalyze peptide cyclization under physiological or mild conditions. This method offers high chemoselectivity, enabling precise control over cyclization sites and product homogeneity. It is increasingly favored for the production of complex cyclic peptide libraries and therapeutic candidates [4]

2.1.2 Conformational Rigidity and Structural Motifs

Cyclization significantly restricts the conformational entropy of peptides, promoting the formation of well-defined secondary structural elements such as β-turns, γ-turns, and helix-like motifs, even in the absence of extended helical or sheet architectures. This conformational preorganization contributes to enhanced binding affinity and specificity by minimizing the entropic cost [6].

This is how macrocyclic peptides often occupy a unique chemical space, larger than typical small molecules but more compact and less immunogenic than biologics.
Cyclic peptides can also mimic structural epitopes of native proteins, particularly protein secondary structures involved in PPIs. This enables them to function as potent modulators or inhibitors of PPIs.

2.1.3 Physicochemical Properties

The ring structure and side-chain composition of cyclic peptides influence several key properties:

• Proteolytic Stability: Cyclization enhances proteolytic stability by protecting peptide termini from exopeptidases and imposing conformational rigidity that reduces accessibility by endopeptidases
• Lipophilicity vs. Hydrophilicity: Balancing polar (e.g., arginine, lysine) and non-polar residues can modulate membrane permeability. Recent studies demonstrate that specific amphipathic architectures combined with intramolecular hydrogen bonding networks can effectively mask polar functionalities, facilitating passive transmembrane diffusion
• Oral Bioavailability: While still uncommon, a few naturally occurring cyclic peptides like cyclosporine A exhibit oral activity [7]. Contemporary design approaches, such as N-methylation and conformational backbone shielding, are employed to enhance membrane permeability and metabolic stability, thereby improving the potential for synthetic cyclic peptides to achieve oral delivery
• Solubility: The solubility is highly dependent on the amino acid sequence and the overall polarity of the peptide. To optimize aqueous solubility and improve pharmacokinetic profiles, chemical modifications, such as PEGylation or lipidation, are frequently employed.  PEGylation improves aqueous solubility, enhances systemic circulation, and increases stability by shielding peptides from enzymatic degradation and renal clearance. In contrast, lipidation typically reduces aqueous solubility but enhances membrane interaction, stability, and albumin binding, thereby prolonging half-life. These strategies are selectively employed based on the desired balance between solubility, stability, and bioavailability

2.2. Chemical Modification Strategies

Chemical modifications are essential for translating cyclic peptides into drug-like molecules suitable for clinical use. Below are key strategies widely employed in both natural product optimization and synthetic peptide engineering:

2.2.1 N-Methylation

N-methylation involves substituting the hydrogen atom of the peptide backbone's amide group with a methyl group. This modification:

• Increases protease resistance by reducing hydrogen bonding with water and proteolytic enzymes
• Enhances lipophilicity and membrane permeability by limiting the number of hydrogen bond donors
• Helps constrain conformational flexibility, promoting bioactive conformations

Notably, cyclosporine A, a naturally occurring cyclic peptide with oral bioavailability, contains multiple N-methylated residues, contributing to its passive membrane permeability [8].

2.2.2 Incorporation of D-Amino Acids

Replacing L-amino acids with D-enantiomers at specific positions can:

• Increase proteolytic stability by making the peptide resistant to enzymatic degradation
• Alter the overall 3D conformation, which can enhance or maintain bioactivity
• Improve in vivo half-life without significantly affecting receptor binding

2.2.3 Use of Non-Natural Amino Acids

D-amino acid scanning is a common strategy in cyclic peptide library design to optimize pharmacokinetic and drug-like properties [9].

Introduction of non-canonical amino acids such as fluorinated residues, β-amino acids or aza-amino acids expands chemical diversity and allows fine-tuning of [10]:

• Hydrophobicity and electrostatic interactions
• Binding affinity to novel or difficult targets
• Structural rigidity and resistance to degradation

This strategy has been instrumental in advancing peptide ligands targeting intracellular PPIs, including key complexes like MDM2-p53 and members of the BCL2 family [11, 12].

2.2.4 PEGylation and Lipidation

PEGylation (attachment of polyethylene glycol chains) and lipidation (attachment of fatty acid chains) are used to modulate pharmacokinetics:

• PEGylation improves solubility, circulation half-life, and stability by shielding the peptide from renal clearance and immune recognition
• Lipidation enhances membrane interaction and serum albumin binding, thereby increasing half-life and cellular uptake

Examples include semaglutide, a lipidated GLP-1 analogue, which benefits from extended plasma half-life due to albumin binding [13]. Another example is APL-2, a PEGylated cyclic peptide that inhibits complement component C3 and is undergoing investigation for the treatment of complement-mediated diseases [14].

2.2.5 Peptide Stapling and Bridging

Peptide stapling involves the introduction of covalent cross-links (often hydrocarbon staples) between side chains to:

• Stabilize α-helical or looped conformations
• Enhance protease resistance
• Increase membrane permeability and cellular uptake

While originally developed for linear peptides, stapled cyclic peptides represent a hybrid strategy combining macrocyclization with intramolecular bridging to maintain bioactive conformations under physiological conditions [15].
Recent advances include photo-switchable bridges and metal-coordination-based staples, enabling spatial or temporal control of activity and being useful in cancer and neurobiology research [16].

2.3 Emerging Trends

• Cyclization via click chemistry and enzymatic ligation (e.g., butelase-mediated macrocyclization) is being explored for site-specific and biocompatible cyclization [17, 18]
• Backbone modification (e.g., N-substituted glycines or peptoids) allows for customizable pharmacokinetics and target selectivity
• Antibody-peptide conjugates are being explored to combine targeting specificity with cyclic peptide bioactivity

These chemical strategies are critical, not only for therapeutic optimization but also for expanding the accessible chemical space for high-throughput screening and rational drug design. Together, they enhance the potential of cyclic peptides to succeed where traditional molecules fail.

3. Applications of Cyclic Peptides

Cyclic peptides have significant potential across therapeutic and research domains.

3.1 Therapeutic Applications

3.1.1 Targeting PPIs

Many diseases, including cancer, neurodegeneration, and autoimmune disorders, are driven by dysregulated PPIs. Cyclic peptides are well-positioned to overcome this limitation. Examples include:

• ALRN-6924, a stapled α-helical peptide developed by Aileron Therapeutics, mimics the p53-binding motif to competitively inhibit MDM2, thereby restoring p53 activity in cancer cells [11]. It has progressed through Phase I and II clinical trials for various solid tumors and hematologic malignancies
• BH3-mimetic cyclic peptides, though mostly in preclinical or early-stage development, are being explored by academic labs and biotech companies to target anti-apoptotic BCL-2 family proteins, promoting programmed cell death in cancer cells [12]

3.1.2 Antimicrobial and Antiviral Agents

Many naturally occurring and synthetic cyclic peptides exhibit antimicrobial activity, often through disruption of bacterial membranes or inhibition of essential enzymes. Examples include:

• Gramicidin S and bacitracin (classic antimicrobial cyclic peptides) [19]
• Macrocyclic glycopeptides used against methicillin-resistant staphylococcus aureus and drug-resistant gram-positive pathogens [20]
• Cyclic peptide inhibitors of viral proteins (e.g., HIV-1 fusion inhibitors, SARS-CoV-2 spike blockers) are being explored in antiviral pipelines [21]

3.1.3 Cancer Vaccines and Immunotherapy

Cyclic peptides are increasingly being investigated in the context of personalized immunotherapy. Their ability to structurally mimic native epitopes or tumor-specific neoantigens makes them effective in inducing both T-cell-mediated and antibody-mediated immune responses [22].

• Neoantigen-based vaccines: Cyclic peptides incorporating tumor-specific mutations exhibit improved MHC binding and stability, enhancing CD8⁺ T-cell activation. Also, cytotoxic CD4⁺ T cells have been shown to produce perforin and granzyme B, broadening the immune effector repertoire beyond conventional CTLs [22, 23]
• HER2/EGFR mimetics: Cyclized B-cell epitope mimetics derived from HER2 or EGFR trigger neutralizing antibody responses that block receptor dimerization and inhibit tumor cell signaling. These vaccines may also promote T-helper responses critical for durable B-cell immunity [24]
• Cyclopeptide mimotopes: Mimics of tumor-associated carbohydrate or glycopeptide antigens, presented in a cyclic format, exhibit enhanced stability and immunogenicity in preclinical models of breast, pancreatic, and colorectal cancer. These can engage CD4⁺ T cells and B cells, generating coordinated cellular and humoral responses [25]
• Self-adjuvanting cyclic vaccines: Peptides conjugated to immune stimulants (e.g., CpG, lipid moieties) improve antigen presentation and facilitate the immune activation in tumor regression  [26]

Emerging platforms also integrate cyclic peptides into liposomes, nanoparticles, or virus-like particles for enhanced delivery and presentation to the immune system [27]. These approaches are being explored for use in renal cell carcinoma, melanoma and glioblastoma, especially when combined with checkpoint blockade therapies.

3.1.4 Autoimmune and Inflammatory Disorders

Cyclic peptides have shown promise in modulating inflammatory signaling pathways and immune checkpoints [28].

• IL-17 and TNF-α pathway inhibitors for rheumatoid arthritis and psoriasis.
• Antagonists of chemokine receptors or co-stimulatory molecules to reduce autoimmune T-cell activation.

3.2 Cyclic Peptide Libraries and High-Throughput Screening

Cyclic peptide libraries are essential tools in the discovery and optimization of new peptide-based therapeutics. These libraries consist of vast collections of diverse cyclic peptides, varying in sequence, ring size, and chemical modifications, enabling broad screening against biological targets.
The diversity of these libraries is crucial, as it increases the likelihood of identifying high-affinity binders to challenging targets. Diversity can be introduced through randomized amino acid sequences, incorporation of non-natural amino acids, and variable cyclization chemistries. Common approaches for generating these libraries include:

• Phage display, where peptide sequences are expressed on the surface of bacteriophages and selected for target binding [29]
• mRNA display, a cell-free system that links phenotype (peptide) to genotype (mRNA), allowing for very large library sizes [30]

These screening methods are pivotal in the hit identification phase of drug discovery, where initial lead peptides are selected based on binding affinity, specificity, and functional activity. Once identified, these hits undergo iterative cycles of optimization through structure–activity relationship (SAR) studies, often supported by computational modeling and biophysical characterization.

4. Synthesis of Cyclic Peptides

The synthesis of cyclic peptides is a cornerstone in the development of peptide-based therapeutics. The process typically involves the generation of a linear peptide precursor followed by a cyclization step that forms a stable covalent bond between terminal or side-chain functionalities.

4.1 Synthesis of linear precursors

The most widely used method for synthesizing linear peptide precursors is Solid-Phase Peptide Synthesis (SPPS) due to its automation capability, high yield and compatibility with a wide range of amino acid derivatives.

• Fmoc/tBu chemistry is typically employed, where the N-terminus is protected by Fmoc (removed under basic conditions) and side chains are protected by acid-labile groups [31]
• After linear peptide assembly, the peptide is cleaved from the resin (with or without side-chain deprotection, depending on the cyclization strategy) and purified by HPLC

SPPS allows the precise incorporation of non-natural amino acids, such as aza-amino acids, D-amino acids and click-compatible residues (e.g., azide or alkyne groups). These modifications are critical for tuning biological activity and stability [32].

4.2 Chemical Cyclization

Chemical cyclization is a critical step that converts a linear peptide into a cyclic form. Common strategies include:

• Head-to-tail/Backbone cyclization: For this, the peptide must first be fully deprotected at both termini. Common coupling reagents include HATU, HBTU, DIC, or EDC, used with DIPEA as a base, in solvents like DMF or DMSO. This method works best for peptides 5-12 residues long [33]
• Side-chain-to-side-chain cyclization: Common examples include amide bonds between Lys and Glu/Asp, disulfide bridges between Cys residues (via oxidative folding using DMSO), and thioether linkages using Cys with maleimide groups. This strategy enhances structural stability without involving the peptide termini [4]
• Click chemistry: This involves a Cu(I)-catalyzed azide–alkyne cycloaddition to form stable triazole linkages. Azide- or alkyne-functionalized amino acids are introduced during SPPS. The reaction uses CuSO₄ with sodium ascorbate as the catalyst and proceeds under mild, bio-orthogonal conditions with high specificity [17]
• Lactam and lactone cyclization: This involves forming amide (lactam) or ester (lactone) bonds between side chains. Common residue pairs include Asp/Glu with Lys or ornithine for lactam formation and Ser/Thr with Asp/Glu for lactones [34]
• Ring-closing metathesis: This uses olefin-bearing amino acids and Grubbs' catalysts to form carbon–carbon double bonds. It is typically performed in solvents like dichloromethane or toluene. This creates stable hydrocarbon-stapled peptides that enhance helicity and structural stability [34]

4.2 Enzymatic Cyclization

Nature often utilizes enzymes to produce highly stable cyclic peptides with complex topologies [18]. These approaches are increasingly adopted in synthetic peptide engineering.

• Sortase A, Butelase 1, and inteins are used to catalyze peptide cyclization under mild conditions with high regioselectivity
• Enzymatic methods offer fewer side reactions, compatibility with aqueous buffers, and selective labeling or cyclization at specific recognition motifs

These tools are particularly useful in bioconjugation and in vivo peptide engineering.

Supported by improvements in SPPS, the synthesis of cyclic peptides has advanced significantly. Moreover, the introduction of bio-orthogonal linkers and enzyme-assisted cyclizations has fueled the field further. Each method offers unique advantages in terms of yield, selectivity, and structural diversity.

5. Challenges in Cyclic Peptide Development

Despite their growing promise as therapeutic agents, cyclic peptides face several scientific and technical hurdles that limit their translation into clinically approved drugs. Addressing these challenges requires interdisciplinary innovation spanning synthetic chemistry, drug delivery, and screening technologies.

5.1 Synthetic Complexity and Yield Limitations

The cyclization of peptides often involves intricate synthetic procedures that demand precise control over reaction conditions. Key issues include:

• Low cyclization efficiency, especially for long or sterically hindered sequences
• Side reactions such as oligomerization, epimerization, or aspartimide formation.
• Purification difficulties due to closely related side-products or isomers

Furthermore, the synthesis of peptides that contain non-natural amino acids or chemically stapled peptides may require multi-step protocols that reduce overall yield and increase cost.

5.2 Library Screening and Hit Identification

The discovery of functional cyclic peptides often relies on screening large combinatorial libraries. However:

• Cyclization limits conformational diversity, which can reduce hit frequency
• Display platforms (e.g., phage display, mRNA display) require sophisticated adaptation to accommodate cyclized structures
• False positives/negatives can arise due to peptide aggregation, nonspecific binding, or instability under screening conditions

Additionally, maintaining peptide integrity (e.g., disulfide bridges) during screening adds complexity to assay development.

5.3 Scalability and Manufacturing

While peptide synthesis has been industrialized on a large scale, cyclic peptides, especially those with multiple modifications or complex folding patterns, present scalability issues:

• Batch variability, cost-intensive reagents, and lengthy purification steps are key bottlenecks
• Regulatory hurdles concerning manufacturing consistency, stability, and formulation must also be addressed for clinical translation

However, ongoing advances in automated synthesis, structure-guided design, and novel delivery technologies hold promise for overcoming these barriers and unlocking the full therapeutic potential of this unique molecular class.

6. Future Outlook

The field of cyclic peptides is rapidly evolving, driven by advances in synthetic chemistry, high-throughput screening, and computational design. Emerging techniques such as automated flow-based peptide synthesis, enzymatic macrocyclization, and mRNA display of macrocycles are enhancing library diversity and production efficiency. Additionally, integration with AI-driven drug design is streamlining hit optimization and SAR analyses.

Looking ahead, cyclic peptides hold great promise in targeted therapies, especially for oncology, neurodegenerative diseases, and antimicrobial resistance. Their ability to disrupt intracellular protein–protein interactions makes them strong candidates for previously undruggable targets. As delivery technologies and structure-based design improve, cyclic peptides are poised to become a key modality in next-generation therapeutics.

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