How Cyclization Changes Peptide Behavior: Conformational Preorganization, Skin Delivery, and Integrin Binding, Using Cyclopeptide-5 as an Example

Introduction

Skincare peptides generally interact with receptors, enzymes, or other proteins through specific amino acid sequences and spatial conformations, thereby regulating the behavior of skin cells.

For a peptide to progress from a formulation ingredient to a detectable effect in the skin, it generally needs to undergo the following sequence of processes:

Remain intact in the formulation → be released from the formulation matrix or carrier → enter a skin region where it can access the target → maintain a three-dimensional conformation suitable for target recognition → interact with a receptor or enzyme → induce cellular and tissue-level changes

During this process, linear peptides may undergo proteolytic degradation or may have difficulty consistently presenting their active side chains because of a broadly distributed conformational ensemble. Molecular weight, polarity, ionization state, and hydrogen-bonding capacity may also restrict their passage through the stratum corneum.

Cyclization can alter the terminal state and conformational distribution of a peptide chain and rearrange the spatial positions of polar groups and hydrophobic side chains. The properties of a cyclic peptide depend not only on whether a closed ring is formed, but also on ring size, amino acid sequence, stereochemistry, cyclization site, intramolecular hydrogen bonding, and the delivery system.[1–3]

1 What Is a Cyclic Peptide? Cyclization Is Not Limited to Head-to-Tail Linkage

Cyclic peptides are a class of peptides in which the peptide chain forms a closed structure through one or more covalent linkages. Conventional linear peptides have a free amino terminus, or N-terminus, and a free carboxyl terminus, or C-terminus. In cyclic peptides, all or part of the peptide chain forms a ring through linkages involving the backbone or side chains.

Common cyclization modes include:

Cyclization mode	Linkage	Main structural characteristics
Head-to-tail cyclization	The N-terminal amino group forms an amide bond with the C-terminal carboxyl group	Eliminates both free termini and forms a closed backbone
Head-to-side-chain cyclization	The N-terminus is linked to an amino acid side chain	Restricts the local conformation while retaining the C-terminus
Tail-to-side-chain cyclization	The C-terminus is linked to a side chain	Restricts the local conformation while retaining the N-terminus
Side-chain-to-side-chain cyclization	Two side chains form a lactam, disulfide, thioether, or another linkage	The N-terminus and C-terminus may remain free
Nonpeptidic bridge cyclization	Ring closure through a hydrocarbon chain, triazole, or another chemical bridge	Can modulate rigidity, hydrophobic surface area, and chemical stability

When all covalent linkages within the closed ring are amide-type peptide bonds, the structure is referred to as a homodetic cyclic peptide. RonaCare® Cyclopeptide-5 is a homodetic cyclic peptide in which all building units within the closed backbone are connected through amide-type peptide bonds.[1,7,9]

Cyclization changes more than the overall shape of the molecule. It can also alter backbone turns, side-chain orientation, terminal charge, hydrogen-bond distribution, and the mode of target binding. Peptides with identical or similar amino acid compositions may exhibit different stability, affinity, and receptor selectivity when they differ in ring size, cyclization site, or stereochemistry.[1,6]

2 Why Linear Skincare Peptides May Lose Activity

2.1 Free Termini May Serve as Entry Points for Enzymatic Degradation

Many linear peptides without terminal capping contain free N- and C-termini. Exopeptidases can progressively remove amino acids from the ends of the peptide chain, whereas endopeptidases can recognize and hydrolyze specific internal peptide bonds.

For signaling peptides that depend on an intact sequence for receptor binding, the loss of only a few amino acid residues may alter the distance and orientation between key side chains and reduce the original recognition capability.

Head-to-tail cyclization connects the N- and C-termini through a new amide bond, thereby reducing the opportunity for certain exopeptidases to initiate degradation from the termini. Backbone turns and steric shielding created by ring closure may also reduce the accessibility of susceptible peptide bonds to some endopeptidases.[2]

Cyclic peptides still contain multiple peptide bonds and may be hydrolyzed by proteases capable of recognizing their exposed structural features. The proteolytic stability of some cyclic peptides generally results from the combined effects of cyclization, D-amino acids, non-natural amino acids, and three-dimensional conformation rather than from ring closure alone.

2.2 The Proportion of Active Conformations May Be Low in Linear Peptides

Linear peptides contain multiple rotatable single bonds in their backbones and side chains. In solution, a given peptide chain generally exists as an ensemble of interconverting three-dimensional conformations rather than maintaining a single shape.

A receptor-binding site can accommodate only a subset of these conformations. When a linear peptide approaches a receptor, it must adopt a backbone shape close to the bound state and then further adjust the positions of its key side chains. If active conformations account for only a small fraction of the total conformational ensemble, the proportion of molecules capable of entering the receptor-binding site directly will also be correspondingly low.

Structural information involved in receptor recognition includes:

① the distance between key side chains;

② the spatial distribution of positive and negative charges;

③ backbone turns and peptide-bond orientation;

④ the orientation of hydrophobic groups;

⑤ shape complementarity between the ligand and receptor-binding surfaces.

Structure–activity studies of cyclic arginine–glycine–aspartic acid peptides have shown that different ring sizes and preorganized conformations can alter the binding ability and selectivity of peptides toward integrins such as αIIbβ3, αvβ3, and α5β1.[6]

2.3 Activity in Cell-Based Experiments Does Not Equal Skin Accessibility

The stratum corneum consists of corneocytes and highly organized intercellular lipids and is the principal barrier to the entry of topical ingredients into the viable epidermis and dermis.

Peptide molecules generally have the following characteristics:

① a molecular weight higher than that of common small-molecule active ingredients;

② multiple amide bonds;

③ multiple hydrogen-bond donors and acceptors;

④ side chains that may become ionized under physiological skin conditions;

⑤ potentially limited partitioning into stratum corneum lipids.

The empirical “500 Da rule” states that compounds with molecular weights above approximately 500 Da generally have difficulty undergoing sufficient passive diffusion through an intact stratum corneum. This is an empirical rule rather than an absolute physical boundary. Molecular conformation, polarity, ionization state, formulation composition, and skin condition also affect actual delivery outcomes.[4]

3 How Cyclization Changes Stability and Conformation

3.1 Cyclization Reduces Terminal Exposure

Head-to-tail cyclization eliminates the free N- and C-termini, so the peptide chain no longer contains termini that can be directly recognized by certain exopeptidases. Ring closure also changes the spatial exposure of peptide bonds, making some cleavage sites less accessible to protease-binding regions.

This improvement in stability depends on sequence and conformation. Ring size, local flexibility, exposed peptide bonds, and the presence or absence of D-amino acids or non-natural amino acids all affect actual resistance to proteolysis.[2]

Linear peptides can also be stabilized through N-terminal acylation, C-terminal amidation, fatty-acid modification, or the incorporation of non-natural amino acids. Cyclization is one strategy for optimizing peptide structure, but it is not the only method for stabilizing linear peptides.

3.2 Conformational Preorganization Brings the Peptide Chain Closer to the Receptor-Required Shape

Peptides are not static structures in solution. The backbone and certain side chains on either side of peptide bonds can rotate, allowing the same peptide to adopt multiple three-dimensional conformations over time. A receptor can generally recognize only a subset of these conformations effectively because receptor binding depends not only on amino acid sequence but also on the distance, orientation, and charge distribution of key side chains.

Linear peptides generally have relatively high conformational freedom and can sample a broad conformational range. Only some of these conformations approximate the shape required by the receptor-binding site. During receptor binding, the peptide chain must form or select a relatively well-matched conformation from this ensemble and then further adjust the positions of key side chains.

Cyclization restricts the conformational space accessible to the peptide chain. If the conformations frequently adopted after cyclization resemble the receptor-bound conformation, a larger proportion of peptide molecules may already possess a spatial arrangement suitable for binding before approaching the receptor. This phenomenon is known as conformational preorganization.[1,3]

Conformational preorganization can be summarized as follows:

Linear peptide	Preorganized cyclic peptide
Broad accessible conformational range	Restricted accessible conformational range
Conformations close to the receptor-bound shape may account for only a small proportion	Conformations close to the receptor-bound shape may account for a higher proportion
Usually requires greater conformational adjustment before binding	May require less conformational adjustment before binding
Positions and orientations of key side chains vary substantially	Positions and orientations of key side chains are relatively concentrated

When cyclization preorganizes the free peptide into a conformation close to that required by the receptor, the unfavorable entropic contribution associated with restricting peptide-chain conformational freedom during receptor binding may be reduced. Key side chains may also be more likely to form ionic interactions, hydrogen bonds, and hydrophobic contacts simultaneously.[1,6] Studies of cyclic RGD peptides have shown that changes in ring size, stereochemistry, and solution conformation can alter their binding ability and selectivity toward different integrins.[6]

The effect of preorganization depends on whether the conformation produced by cyclization matches the target. If cyclization stabilizes a conformation that is unsuitable for receptor binding, affinity may decrease. Therefore, restricting conformation through cyclization does not automatically increase activity. The key consideration is whether the enriched conformations approximate the binding shape required by the receptor.

3.3 The Effect of Cyclization on Receptor Affinity Depends on Conformational Matching

Cyclization restricts the conformational range accessible to the peptide chain, but its effect on receptor affinity depends on how well the predominant post-cyclization conformation matches the receptor-binding site. If key side chains adopt appropriate distances and orientations in frequently populated conformations, less conformational adjustment may be required before binding, and receptor affinity or selectivity may improve. If key side chains are displaced from the receptor-binding region, affinity may decrease.

A ring that is too small may introduce substantial ring strain and place the backbone and side chains in unfavorable spatial positions. A ring that is too large may retain considerable flexibility, weakening the conformational restriction. The cyclization site, arrangement of L- and D-amino acids, geometry of non-natural amino acids, side-chain charge and hydrophobicity, and intramolecular hydrogen bonding all affect the predominant conformation of a cyclic peptide and its mode of receptor binding.

Cyclization modulates the conformational distribution of the peptide chain and changes the populations of particular conformations. It does not necessarily increase receptor affinity or biological activity.[1,3]

4 How Cyclic Peptides Are Formed and What Affects Cyclization Yield

4.1 Basic Process of Head-to-Tail Cyclization

In the chemical synthesis of head-to-tail cyclic peptides, a protected linear precursor is generally first prepared by solution-phase peptide synthesis or solid-phase peptide synthesis. The N- and C-termini are then selectively exposed to enable intramolecular amidation.

The basic reaction scheme is:

Protected linear peptide

↓ Selective removal of terminal protecting groups

Linear precursor with free N- and C-termini

↓ Activation of the C-terminal carboxyl group and intramolecular nucleophilic attack by the N-terminal amino group

Cyclic peptide with protected side chains

↓ Side-chain deprotection, separation, and purification

Target cyclic peptide

Under conventional conditions, the N- and C-termini do not readily undergo efficient spontaneous dehydration to form a ring. Cyclization generally requires a coupling reagent to activate the C-terminal carboxyl group, allowing the N-terminal amino group of the same molecule to undergo nucleophilic attack and form a new amide bond.[1]

4.2 Intramolecular Ring Closure Competes with Intermolecular Coupling

An activated C-terminus may react with the N-terminus of the same molecule or with the N-terminus of another peptide chain. The latter process produces dimers or oligomers.

Lower reaction concentrations and slow addition generally help reduce intermolecular coupling, although they also increase solvent consumption.

There is no universal cyclization yield for different cyclic peptides. The specific outcome depends on sequence, ring size, protecting groups, reaction concentration, solvent, coupling reagent, and purification criteria.[1]

4.3 Publicly Available Synthesis Information for Cyclopeptide-5

A related patent published by Merck Patent GmbH describes the preparation of several cyclic RGD peptides, including linear peptide assembly, terminal deprotection, intramolecular ring closure, side-chain deprotection, and chromatographic purification. The patent provides chromatographic retention-time and mass-spectrometric identification data for cyclo-(Arg–Gly–Asp–D-Phe–ACHA) and states that related compounds can be prepared by analogy using cyclization and deprotection procedures for the corresponding linear precursors. However, it does not provide an independent, complete account of the quantities used or the final isolated yield for this specific target cyclic peptide.[9]

5 Can Cyclization Improve Skin Delivery?

5.1 Cyclization May Alter Terminal Charge and Apparent Polarity

Head-to-tail cyclization converts the free N-terminal amino group and C-terminal carboxyl group into an amide bond, eliminating two potentially ionizable termini. Some cyclic peptides can also form intramolecular hydrogen bonds, reducing the extent to which certain amide groups are exposed to the solvent and thereby decreasing the polar surface area presented by the molecule.

Some specifically designed cyclic peptides can change conformation in response to the surrounding environment:

Aqueous environment: greater exposure of polar groups, favoring hydration

⇌

Low-polarity or lipid environment: formation of some intramolecular hydrogen bonds and reduced exposure of polar groups

⇌

Membrane–water partitioning of the molecule may change

This environment-dependent conformational behavior is referred to as chameleonic conformational behavior. It depends on the cyclic peptide sequence, stereochemistry, and intramolecular hydrogen-bonding network and is not a property of all cyclic peptides.[3]

Cyclic peptides containing ionizable side chains such as arginine, lysine, aspartic acid, or glutamic acid may still exhibit high effective polarity.

5.2 Cell-Membrane Permeability and Skin Penetration Are Different Processes

Conventional cell membranes are composed primarily of phospholipid bilayers, whereas the stratum corneum consists of corneocytes and ordered ceramides, cholesterol, free fatty acids, and other components. The ability of a cyclic peptide to cross an artificial phospholipid membrane or a cell monolayer does not directly demonstrate that it can cross an intact stratum corneum in the same manner.

The distribution of topically applied ingredients in the skin can be classified as follows:

Process	Meaning
Stratum corneum retention	The active ingredient remains mainly on the skin surface and within the stratum corneum
Intradermal delivery	The active ingredient enters the viable epidermis or localized regions of the dermis
Transdermal absorption	The active ingredient passes through the entire skin and enters the receptor fluid or systemic circulation

If a topical peptide is intended to act on dermal fibroblasts, the intact peptide molecule must enter the dermis and reach a local concentration sufficient to produce a biological response at the site of action. This constitutes intradermal delivery and is not equivalent to transdermal absorption through the entire skin into the bloodstream.

5.3 Whether Cyclopeptide-5 Reaches Its Site of Action Depends on Actual Skin Delivery

Cyclopeptide-5 has a relative molecular mass of 600.67 and contains ionizable groups such as the arginine guanidinium group and the aspartic acid carboxyl group. These structural features confer relatively high polarity and are unfavorable for passive diffusion through the lipid-rich stratum corneum. Cyclization can alter peptide-chain conformation and apparent polarity, but it does not by itself demonstrate that Cyclopeptide-5 can cross the stratum corneum and reach the dermis.[4,8]

Currently available public information includes studies using full-thickness skin models, ex vivo human skin explants, and human formulations. These studies indicate that treatment systems containing Cyclopeptide-5 are associated with changes in certain cellular, tissue, and skin-appearance parameters.[7]

Whether Cyclopeptide-5 can access its targets in the skin depends on its stability in the formulation, release from the carrier, partitioning into the stratum corneum, depth of skin entry, and actual concentration at the site of action. The cyclic structure is only one of the factors influencing skin delivery.

6 Structure of Cyclopeptide-5 and Integrin Recognition

6.1 Molecular Structure

The active structure of RonaCare® Cyclopeptide-5 can be represented as:

cyclo-(Arg–Gly–Asp–D-Phe–ACHA)

The individual building units are:

· Arg: L-arginine;

· Gly: glycine;

· Asp: L-aspartic acid;

· D-Phe: D-phenylalanine;

· ACHA: 1-aminocyclohexane-1-carboxylic acid.

The U.S. Food and Drug Administration Global Substance Registration System (GSRS) lists the systematic name as cyclo(1-aminocyclohexanecarbonyl-L-arginylglycyl-L-α-aspartyl-D-phenylalanyl), with the Unique Ingredient Identifier (UNII) NR327745KQ. The International Nomenclature of Cosmetic Ingredients (INCI) name listed in the Susonity technical information is Cyclotetrapeptide-24 Aminocyclohexane Carboxylate.[7,8]

6.2 Roles of the Individual Structural Units

Structural unit	Structure and role
Arg–Gly–Asp	Constitutes a sequence motif recognized by certain RGD-binding integrins
D-Phe	May influence the local backbone turn and the orientation of the phenyl side chain and may contribute to the design of proteolytic stability
ACHA	Contributes to modulation of ring diameter, ring strain, backbone geometry, and solubility
Closed backbone ring	Eliminates free termini and restricts the conformational range accessible to the RGD sequence

Arginine–glycine–aspartic acid (RGD) is an integrin-recognition motif found in fibronectin, vitronectin, and certain other extracellular matrix proteins.

The 2026 Susonity technical information describes D-Phe as a structural unit that improves binding and enhances proteolytic stability and describes ACHA as a non-natural amino acid unit that modulates ring diameter, ring strain, and solubility.[7]

These effects are based on the stated molecular-design rationale. Publicly available information does not provide complete structure–activity comparisons in which D-Phe or ACHA was individually removed, and the independent contribution of each building unit has not been quantified separately.

6.3 How the Spatial Conformation of RGD Affects Integrin Binding

Certain integrins recognize the arginine–glycine–aspartic acid (RGD) motif in extracellular matrix proteins. Integrins consist of α and β subunits. Their extracellular binding regions can interact with RGD ligands and connect the extracellular matrix to the cytoskeleton and associated signaling processes.[5] RGD ligands generally bind within a binding region jointly formed by the α and β subunits of the integrin.

Integrin recognition of RGD depends not only on the sequence of the three amino acids but also on the spatial positions of their side chains. The guanidinium group of arginine and the carboxyl group of aspartic acid interact with different regions. Their distance, orientation, and overall conformation affect the degree of matching between RGD and the integrin-binding region. The small side chain of glycine facilitates formation of the local turn required for RGD binding.[6] Structural studies of integrin–RGD complexes have shown that RGD is positioned between the head regions of the integrin α and β subunits and contacts both subunits.[5]

The closed backbone ring, D-Phe, and 1-aminocyclohexane-1-carboxylic acid (ACHA) in Cyclopeptide-5 may influence integrin-binding behavior by modulating ring size, backbone geometry, and the conformational distribution of the RGD motif.[6,7] Currently available public information does not provide a solution-conformation analysis of Cyclopeptide-5 itself or the structure of a Cyclopeptide-5–integrin complex. The explanation above is therefore a structural inference based on studies of related cyclic RGD peptides.

It should be noted that currently available public information on Cyclopeptide-5 mainly provides competitive-binding data obtained with isolated integrins. These structural relationships alone cannot determine which cell type mediates its effects in the skin. The cellular distributions of αvβ3, αvβ5, and αvβ6 differ, and αvβ6 is primarily associated with epithelial cells.[5,10]

6.4 Competitive Binding of Cyclopeptide-5 to Integrins

Publicly available technical information describes competitive-binding assays using isolated integrins to compare the effects of Cyclopeptide-5 and a linear RGD pentapeptide on the binding of natural ligands to the αvβ3, αvβ5, and αvβ6 integrins. The half-maximal inhibitory concentration (IC₅₀) is the concentration of the test peptide required to reduce natural-ligand binding by 50%. For the same receptor subtype under identical assay conditions, a lower IC₅₀ indicates greater potency in inhibiting natural-ligand binding.[7]

Test peptide	αvβ3 IC₅₀	αvβ5 IC₅₀	αvβ6 IC₅₀
Linear RGD pentapeptide control	>10,000 nM	>10,000 nM	>10,000 nM
Cyclopeptide-5	41.3 nM	2,970 nM	335 nM

Under these assay conditions, the IC₅₀ values of Cyclopeptide-5 for αvβ3, αvβ5, and αvβ6 were 41.3, 2,970, and 335 nM, respectively. The linear RGD pentapeptide did not achieve 50% inhibition within the tested concentration range.[7] Because the assay systems used for the different integrin subtypes were not completely identical, these values should not be used directly as the basis for a strict cross-subtype ranking of absolute binding affinity.

The results indicate that Cyclopeptide-5 can compete with ligands for the tested integrins. However, they do not establish whether Cyclopeptide-5 functions as a receptor agonist or antagonist in intact skin cells, nor do they identify a specific intracellular signaling pathway.

7 Research Results for Cyclopeptide-5 in Skin Models, Ex Vivo Skin, and Human Formulations

Currently available public information has evaluated Cyclopeptide-5 at three levels: full-thickness skin models, ex vivo human skin, and human formulations. These studies examined gene expression, histological parameters, and human skin parameters, respectively. They provide supporting results at different levels but do not directly constitute a fully validated causal pathway.

All specific experimental data presented in this section are derived from product technical information published by Susonity[7] rather than from independent peer-reviewed studies.

7.1 Matrix-Related Gene Expression in a Full-Thickness Skin Model

The technical information describes the use of a human full-thickness skin model containing keratinocytes and fibroblasts. The model was treated with 0.5 μM, approximately 0.3 ppm, Cyclopeptide-5 for 48 hours. RNA was then extracted, and gene expression was analyzed using a skin-focused microarray. The experiment was performed in triplicate.[7]

Representative results are shown below:

Gene	Encoded product	Change in messenger RNA expression
COL4A1	Type IV collagen α1 chain	Increased by approximately 50%
LAMA4	Laminin α4 chain	Increased by approximately 60%
MMP-13	Matrix metalloproteinase-13	Decreased by approximately 47%
MMP-7	Matrix metalloproteinase-7	Decreased by approximately 40%

COL4A1 and LAMA4 encode basement membrane-related proteins, whereas MMP-13 and MMP-7 participate in the processing and degradation of extracellular matrix components. These results indicate that Cyclopeptide-5 treatment altered the messenger RNA expression of certain genes related to the basement membrane and matrix remodeling.[7]

These data represent gene-expression results and cannot be directly equated with increased amounts of type IV collagen or laminin. They also do not demonstrate direct inhibition of MMP-13 or MMP-7 enzymatic activity. Because the model contained both keratinocytes and fibroblasts, the experiment did not attribute the expression changes to a specific cell type.

7.2 Elastic-Fiber Parameters in Ex Vivo Human Skin

The technical information describes the use of an ex vivo skin explant obtained from a 37-year-old female donor. The skin was treated topically with a caprylic/capric triglyceride–ethanol system containing either 0 or 0.3 ppm Cyclopeptide-5. The experiment lasted 10 days, with six applications in total. The dermal elastic-fiber network was subsequently examined by immunostaining and image analysis.[7]

Compared with the control group, the area occupied by elastic fibers in the dermis increased by approximately 35% in the Cyclopeptide-5-treated group.[7]

This result indicates that a histological parameter of the elastic-fiber network changed in this ex vivo skin model. An increase in stained area alone does not demonstrate increased elastic-fiber synthesis and cannot distinguish among new fiber formation, preservation of existing fibers, or rearrangement of fiber structures. Because the experiment used skin from only one donor, it should be interpreted as an observation from a specific ex vivo model.

7.3 Human Complete-Formulation Study

The technical information includes a human split-face study of RonaCare® Cyclopeptide-5 Alcohol-free. The study enrolled 48 women aged 45–65 years. The test products included a blank emulsion, an oil-in-water emulsion containing 2% RonaCare® Cyclopeptide-5 Alcohol-free, and an emulsion containing 3% of a control peptide ingredient. Each participant applied two randomly assigned products to opposite sides of the face twice daily for 56 days. Each product was tested in 24 participants.[7]

According to the technical information, after 56 days of use of the formulation containing 2% RonaCare® Cyclopeptide-5 Alcohol-free:

① the maximum depth of larger wrinkles in the crow’s-feet area decreased by up to approximately 15%;

② the sagging-volume parameter in the jawline and submental area decreased by up to approximately 9%;

③ the stratum corneum hydration parameter increased by up to approximately 22%.

The 2% value refers to the amount of the commercial blended ingredient added to the formulation, corresponding to approximately 2 ppm active Cyclopeptide-5. It does not mean that the formulation contained 2% pure cyclic peptide.[7]

This study evaluated a complete emulsion containing the Cyclopeptide-5 blended ingredient. Because the commercial ingredient also contains glycerol, lecithin, and ectoin, the human results cannot be attributed entirely and independently to pure Cyclopeptide-5.

7.4 How the Current Evidence Should Be Interpreted

Experimental level	Main result
Full-thickness skin model	Expression of certain genes related to the basement membrane and matrix remodeling changed
Ex vivo human skin	The area occupied by dermal elastic fibers changed
Human formulation study	Wrinkle, facial-contour, and stratum corneum hydration parameters changed

These findings support an association between Cyclopeptide-5 and skin-matrix or appearance-related parameters at different experimental levels. However, they do not demonstrate that every step from integrin binding and gene-expression changes to elastic-fiber changes and human skin outcomes has been established as a complete causal pathway.

8 Classification and Research Applications of Representative Chemicals Related to Cyclic-Peptide Conformational Preorganization, Synthetic Cyclization, Skin Delivery, and Integrin Binding

Note: The following products include core cyclic peptides and RGD reference peptides, amino acids and protected synthetic building blocks, peptide-coupling and macrocyclization reagents, and materials used to study lipid delivery and extracellular matrix mechanisms. These products are used for raw-material analysis, peptide synthesis, structure–activity relationship studies, integrin-binding assays, skin-delivery models, or extracellular matrix evaluation. They are not necessarily all suitable for direct use in cosmetic formulations.

Table 1. Core Cyclic Peptides, RGD Sequence Controls, and Extracellular Matrix Research Materials

Classification	CAS No.	Aladdin Catalog No.	Name	Specification or purity	Product features and applications
Core cyclic-peptide active ingredient	197172-76-2	C1428133	Cyclopeptide-5	—	Used to study cyclic arginine–glycine–aspartic acid structures, conformational preorganization, integrin binding, and skin matrix-related effects.
Linear RGD sequence control	99896-85-2	A427230	Arg-Gly-Asp	10 mM in water	Used to study integrin binding and cell adhesion of the basic linear arginine–glycine–aspartic acid sequence and the structure–activity relationships of linear and cyclic RGD peptides.
Cyclic RGD conformational control	161552-03-0	C419974	Cyclo(-RGDfK)	≥95%	Used to study conformational restriction, integrin affinity, receptor selectivity, and cell adhesion of cyclic arginine–glycine–aspartic acid peptides.
Cyclic RGD integrin-ligand control	188968-51-6	C767522	Cilengitide (EMD 121974)	Moligand™, ≥90%	Used to study the conformation of cyclic peptides containing N-methyl amino acids, αv-class integrin binding, competitive inhibition, and receptor-dependent mechanisms.
Natural RGD ligand	86088-83-7	R283942	Recombinant human fibronectin OsrhFN	For cell culture, ≥95%	Used to study integrin-mediated cell adhesion, spreading, and migration, as well as competitive binding and functional blockade by cyclic RGD peptides.
Natural RGD ligand	83380-82-9	np001007	Vitronectin from human plasma	BioReagent, native, PBS only, ≥95% (SDS-PAGE), see COA	Used to evaluate ligand binding to integrins such as αvβ3 and αvβ5, competitive inhibition, cell adhesion, and cyclic RGD peptide activity.
Basement membrane structural protein	114956-81-9	M1447989	Mouse laminin from EHS mouse sarcoma cells	BioReagent, native, ≥95% (SDS-PAGE), 1.0 mg/mL	Used for basement membrane simulation, cell-culture coating, cell-adhesion studies, and evaluation of cyclic peptide-related extracellular matrix regulation.
Dermal matrix structural protein	9007-34-5	rp335221	Recombinant humanized type III collagen	Animal-origin-free, carrier-free, recombinant, ≥90% (SDS-PAGE), expressed in Nicotiana benthamiana	Used to study dermal collagen networks, extracellular matrix assembly, fibroblast responses, and cyclic peptide-related matrix remodeling.

Table 2. Amino Acids and Protected Synthetic Building Blocks for Cyclic-Peptide Sequences

Classification	CAS No.	Aladdin Catalog No.	Name	Specification or purity	Product features and applications
Arginine monomer for the RGD sequence	74-79-3	A640158	L-Arginine	Animal-origin-free, low endotoxin, Moligand™, for cell culture, ≥99%	Used for arginine–glycine–aspartic acid sequence construction, guanidinium-group recognition studies, cell culture, and structural studies of integrin ligands.
Glycine monomer for the RGD sequence	56-40-6	G274229	Glycine	Moligand™, proteomics grade	Used for RGD sequence construction, backbone-turn modulation, peptide synthesis, and structure–activity studies of cyclic and linear peptides.
Aspartic acid monomer for the RGD sequence	56-84-8	L476204	L-Aspartic acid	UltraBio™, ultrapure grade, ≥99.5% (T)	Used for RGD sequence construction, carboxylic acid side-chain recognition, integrin-ligand synthesis, and peptide-structure studies.
D-amino acid for conformational modulation	673-06-3	P109094	D-Phenylalanine	Moligand™, ≥98%	Used to study cyclic-peptide stereochemistry, backbone turns, aromatic hydrophobic interactions, and proteolytic stability.
Non-natural amino acid for ring-size modulation	2756-85-6	A101237	1-Aminocyclohexane-1-carboxylic acid	≥98%	Used to study Cyclopeptide-5-related ring size, ring strain, local hydrophobic surfaces, and conformational preorganization.
Side-chain-functionalized amino acid	56-87-1	L598932	L-Lysine	Moligand™, ≥98%, metals <500 ppm	Used for cyclic RGD peptide construction, side-chain cyclization, linker introduction, and labeling conjugation.
Protected arginine building block	154445-77-9	F110975	Fmoc-Arg(Pbf)-OH	≥98%	Used to introduce arginine residues in solid-phase peptide synthesis, protect the guanidinium side chain, and construct cyclic RGD peptide precursors.
Protected glycine building block	29022-11-5	F103019	Fmoc-Gly-OH	≥98%	Used to introduce glycine residues in solid-phase peptide synthesis, extend RGD sequences, and prepare linear cyclization precursors.
Protected aspartic acid building block	71989-14-5	F116773	Fmoc-L-aspartic acid β-tert-butyl ester	≥98%	Used for peptide-chain coupling through the α-carboxyl group of aspartic acid, protection of the side-chain carboxyl group, and RGD cyclic-peptide synthesis.
Protected D-phenylalanine building block	86123-10-6	F105835	Fmoc-D-phenylalanine	≥98%	Used to introduce D-phenylalanine residues, modulate cyclic-peptide stereoconformation, and study proteolysis-resistant structures.
Protected ACHA building block	162648-54-6	F181888	1-(Fmoc-amino)cyclohexanecarboxylic acid	≥96%	Used to introduce the Cyclopeptide-5-related non-natural amino acid unit, modulate ring size, and prepare ring-closure precursors.
N-Methyl amino acid building block	84000-11-3	F117124	Fmoc-N-methyl-L-valine	≥98%	Used for N-methylated cyclic-peptide synthesis, peptide-bond conformational restriction, proteolytic stability, and membrane-partitioning studies.
Orthogonally protected lysine building block	71989-26-9	F110978	Nε-Fmoc-Nα-Boc-L-lysine	≥98%	Used for selective deprotection of the lysine side chain, side-chain cyclization, labeling and conjugation, and synthesis of cyclic RGD derivatives.

Table 3. Reagents for Peptide Coupling, Macrocyclization, Deprotection, and Chromatographic Analysis

Classification	CAS No.	Aladdin Catalog No.	Name	Specification or purity	Product features and applications
Mild inorganic base for cyclization	144-55-8	S118660	Sodium bicarbonate	For cell culture, suitable for insect cell culture, ≥99.5%	Used for acid–base adjustment, reaction neutralization, and ring-closure condition screening in intramolecular amidation reactions of cyclic peptides.
Acidic deprotection reagent	76-05-1	T103293	Trifluoroacetic acid (TFA)	For protein sequencing, ≥99%	Used for peptide-resin cleavage, removal of acid-labile side-chain protecting groups, complete deprotection of cyclic peptides, and sample pretreatment.
Reversed-phase chromatographic mobile-phase solvent	75-05-8	A119010	Acetonitrile (ACN)	HPLC gradient grade, chromatographic HPLC grade, ≥99.9%	Used for reversed-phase HPLC separation, purity analysis, preparative purification, and mass-spectrometry mobile-phase preparation for cyclic peptides.
Polar solvent for peptide synthesis	68-12-2	D119450	N,N-Dimethylformamide (DMF)	Anhydrous grade, ≥99.8%	Used for solid-phase peptide synthesis, amino acid coupling, protecting-group removal, and preparation of cyclization reaction systems.
Solvent for peptide synthesis and cyclization	75-09-2	D433567	Dichloromethane	Suitable for analysis, ACS	Used for peptide-resin swelling, protecting-group operations, adjustment of cyclization solvent composition, and sample processing.
Fmoc deprotection reagent	110-89-4	P1506346	Piperidine (controlled precursor chemical)	Biotechnology grade, ≥99.5%	Used for fluorenylmethoxycarbonyl deprotection, stepwise extension of peptide chains in solid-phase synthesis, and preparation of linear cyclic-peptide precursors.
Organic base for coupling reactions	7087-68-5	D109322	N,N-Diisopropylethylamine	Distilled grade, ≥99.5%	Used for peptide-bond coupling, carboxyl-group activation, neutralization of acidic by-products, and adjustment of macrocyclization reaction conditions.
Carbodiimide coupling reagent	693-13-0	N420184	N,N′-Diisopropylcarbodiimide (DIC)	≥98.5%	Used for amino acid condensation, solid-phase peptide-chain extension, linear-precursor preparation, and cyclization-condition screening.
Highly active peptide-coupling reagent	148893-10-1	H109327	O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU)	≥99%	Used for coupling sterically hindered amino acids, synthesizing linear cyclic-peptide precursors, intramolecular amidation, and constructing difficult peptide bonds.
Coupling-reaction additive	3849-21-6	E138773	Ethyl 2-cyano-2-(hydroxyimino)acetate	≥98%	Used in carbodiimide coupling systems to reduce racemization risk, improve peptide-bond formation selectivity, and optimize cyclization conditions.
Fmoc protecting-group introduction reagent	82911-69-1	F106173	9-Fluorenylmethyl N-succinimidyl carbonate	≥98%	Used for fluorenylmethoxycarbonyl protection of amino acids and peptide fragments, preparation of protected building blocks, and selective amino-group protection.
Intramolecular cyclization reagent	26386-88-9	D106412	Diphenyl phosphoryl azide (DPPA)	≥97%	Used for carboxyl-group activation of linear peptides, head-to-tail intramolecular amidation, and investigation of ring-closure routes for related cyclic RGD peptides.

Table 4. Lipid-Delivery Materials, Formulation Carriers, and Auxiliary Materials for Skin Models

Classification	CAS No.	Aladdin Catalog No.	Name	Specification or purity	Product features and applications
Solvent and humectant for alcohol-free systems	56-81-5	G116209	Glycerol	For cell culture, suitable for insect cell culture, ≥99% (GC)	Used in alcohol-free cyclic-peptide blended systems, humectant matrices, solvent environments, and studies of formulation release and skin hydration.
Liposomal membrane-modulating material	57-88-5	C104036	Cholesterol	For cell culture, ≥99% (GC)	Used to study liposomal membrane fluidity, stability, encapsulation and release, and lipid-based delivery systems for cyclic peptides.
Solvent for alcohol-containing systems	64-17-5	E130059	Ethanol	Anhydrous grade, Moligand™, ≥99.5%, H₂O ≤0.005%	Used in alcohol-containing cyclic-peptide blended systems, solvent-composition adjustment, ex vivo skin application, and skin-partitioning studies.
Phospholipid delivery carrier	8002-43-5	P1456010	Phospholipids from sunflower, non-GMO	Natural, with ≥60% phosphatidylcholine	Used to prepare liposomes and phospholipid aggregates, encapsulate cyclic peptides, disperse formulations, and investigate localized skin delivery.
Oil-phase carrier material	65381-09-1	H304294	Mixture of caprylic and capric glycerides	Mixture	Used as an oil-phase carrier for ex vivo topical skin application, cyclic-peptide dispersion, and skin histology experimental systems.
Material for stability and hydration in blended systems	96702-03-3	E292674	Ectoin	≥99%	Used for hydration protection, osmotic regulation, skin-stress models, and formulation-stability studies in cyclic-peptide blended systems.

References

[1] White C J, Yudin A K. Contemporary strategies for peptide macrocyclization. Nature Chemistry, 2011, 3(7): 509–524. DOI: 10.1038/nchem.1062.

[2] Zorzi A, Deyle K M, Heinis C. Cyclic peptide therapeutics: past, present and future. Current Opinion in Chemical Biology, 2017, 38: 24–29. DOI: 10.1016/j.cbpa.2017.02.006.

[3] Linker S M, Schellhaas C, Kamenik A S, Veldhuizen M M, Waibl F, Roth H J, Fouché M, Rodde S, Riniker S. Lessons for oral bioavailability: how conformationally flexible cyclic peptides enter and cross lipid membranes. Journal of Medicinal Chemistry, 2023, 66(4): 2773–2788. DOI: 10.1021/acs.jmedchem.2c01837.

[4] Bos J D, Meinardi M M H M. The 500 Dalton rule for the skin penetration of chemical compounds and drugs. Experimental Dermatology, 2000, 9(3): 165–169. DOI: 10.1034/j.1600-0625.2000.009003165.x.

[5] Pang X, He X, Qiu Z, Zhang H, Xie R, Liu Z, Gu Y, Zhao N, Xiang Q, Cui Y. Targeting integrin pathways: mechanisms and advances in therapy. Signal Transduction and Targeted Therapy, 2023, 8: 1. DOI: 10.1038/s41392-022-01259-6.

[6] Pfaff M, Tangemann K, Müller B, Gurrath M, Müller G, Kessler H, Timpl R, Engel J. Selective recognition of cyclic RGD peptides of NMR-defined conformation by αIIbβ3, αvβ3, and α5β1 integrins. Journal of Biological Chemistry, 1994, 269(32): 20233–20238. DOI: 10.1016/S0021-9258(17)31981-6.

[7] Susonity. RonaCare® Cyclopeptide-5 and RonaCare® Cyclopeptide-5 Alcohol-free: Technical Presentation [EB/OL]. 2026-04-01.

[8] U.S. Food and Drug Administration. Global Substance Registration System: Cyclotetrapeptide-24 Aminocyclohexane Carboxylate, UNII NR327745KQ, Record Version 5 [EB/OL]. 2026-03-03.

[9] Anzali S, Jonczyk A. Compositions containing cyclic peptides and methods of use: US10278911B2 [P]. Assignee: Merck Patent GmbH. 2019-05-07.

[10] Huang X Z, Wu J F, Cass D, Erle D J, Corry D, Young S G, Farese R V Jr, Sheppard D. Inactivation of the integrin beta 6 subunit gene reveals a role of epithelial integrins in regulating inflammation in the lung and skin. Journal of Cell Biology, 1996, 133(4): 921–928. DOI: 10.1083/jcb.133.4.921.

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