Cyclic Dipeptides Research Articles

Cover Feature: Novel Class of Ambipolar Columnar Liquid Crystals Based on Cyclic Dipeptide and Isatin Hybrids (ChemPhysChem 5/2025)

Cover Feature: Novel Class of Ambipolar Columnar Liquid Crystals Based on Cyclic Dipeptide and Isatin Hybrids (ChemPhysChem 5/2025)

Tumor Microenvironment pH-Sensitive Peptidomimetics for Targeted Anticancer Drug Delivery.

Cell-penetrating peptides (CPPs) are known for their effective intracellular transport of bioactives such as therapeutic proteins, peptides, nucleic acid, and small molecule drugs. However, the excessive cationic charges that promote their membrane permeability result in nonselective delivery and cellular toxicity. In this study, we report a decamer cell-penetrating peptidomimetic, Hkd, designed to selectively deliver anticancer drugs into tumor cells in response to the acidic microenvironment. The pH-sensitive histidine (H) imidazole side chain undergoes protonation in acidic environments, facilitating membrane permeability. The rigid cyclic dipeptide (CDP) core (kd) of Hkd has multiple hydrogen bond donor and acceptor sites, enabling selective interaction-driven cellular uptake. Pharmacokinetic studies revealed the excellent serum stability of Hkd. Cellular uptake studies of Hkd showed improved uptake at a lower pH than physiological pH. Conjugation of Hkd to the anticancer drug camptothecin (Cpt) reduced nonselective drug transport to normal cells while effectively delivering the drug into cancerous cells at the tumor microenvironment pH and retaining the therapeutic potential of the drug. The systematic design of pH-sensitive peptidomimetics offers a viable method to overcome the challenges of stability and selectivity faced by traditional highly cationic CPPs, potentially expanding the application range of this delivery system.

In Vitro and In Silico Studies of Maculosin as a Melanogenesis and Tyrosinase Inhibitor.

The investigation of melanogenesis and tyrosinase inhibitors is essential for developing safe and effective natural compounds to treat pigmentation disorders. This study aimed to evaluate the effects of maculosin, a cyclic dipeptide composed of tyrosine and proline, on melanin production and tyrosinase activity using the B16F10 melanoma cell model, while elucidating its mechanism of action through molecular docking and molecular dynamics (MD) simulations. Experimental results demonstrated that maculosin inhibited intracellular melanin content and tyrosinase activity in a concentration-dependent manner in B16F10 melanoma cells. Molecular docking analyses revealed that maculosin exhibited high binding affinities with mushroom tyrosinase (mTYR), tyrosinase-related protein 1 (TYRP1), and Bacillus megaterium tyrosinase (BmTYR) with binding energies of -7.7, -6.8, and -7.5 kcal/mol, respectively. Furthermore, MD simulations confirmed the structural stability and dynamic flexibility of maculosin-protein complexes, as indicated by RMSD, RMSF, Rg, SASA, hydrogen bond interactions, PCA, and DCCM analyses. Binding free energy calculations using the MM/PBSA method showed that maculosin exhibited binding energies of -28.76 kcal/mol with mTYR and -22.23 kcal/mol with TYRP1, outperforming standard co-crystal inhibitors such as tropolone (-12.47 kcal/mol) and kojic acid (-12.73 kcal/mol). Critical residues, including VAL-283 and HIS-263 in mTYR and HIS-381, GLY-389, and THR-391 in TYRP1, were identified as key contributors to maculosin binding, corroborating molecular docking findings and displaying strong correlations in DCCM analyses. Collectively, these results suggest that maculosin is a highly promising candidate for the treatment of pigmentation disorders, offering significant inhibitory effects on melanogenesis and tyrosinase activity.

Geranylation of Cyclic Dipeptides and Naphthols by the Fungal Prenyltransferase CdpC3PT_F253G.

Prenyl modification often improves the biological activities of compounds. Prenyltransferases have attracted attention as environmentally friendly biocatalysts for catalyzing prenyl modification of compounds. Compared to dimethylallyl modifications, research on geranyl modifications is relatively limited. To enrich biocatalytic toolboxes for generating potentially bioactive geranylated derivatives, this study developed methodologies to synthesize two types of geranylated compounds, i. e., geranylated tryptophan-containing cyclic dipeptides and geranylated naphthols, employing the F253G mutant of CdpC3PT, a cyclic dipeptide prenyltransferase from Neosartorya fischeri. The cyclic dipeptides (1-3) were transformed into C7-geranylated products (1G1-3G1), whereas 1-naphthol (4) and derivatives (5-6) yielded C4-geranylated products (4G1-6G1) and 2,7-dihydroxynaphthalene (7) generated a C3-geranylated product (7G1). All seven substrates and their geranylated products underwent antibacterial efficacy testing against Bacillus subtilis. Among them, five geranylated compounds (2G1 and 4G1-7G1) demonstrated antibacterial efficacies against Bacillus subtilis, with MIC values ranging from 4 to 32 μg/mL, surpassing their non-geranylated precursors. This research broadens the tools of geranyl-modifying biocatalysts, illustrates a case for developing highly efficient or function-altered biocatalysts and showcases the potential of prenyltransferases in the biosynthesis of bioactive small molecules.

Broad substrate scope C-C oxidation in cyclodipeptides catalysed by a flavin-dependent filament

Cyclic dipeptides are produced by organisms across all domains of life, with many exhibiting anticancer and antimicrobial properties. Oxidations are often key to their biological activities, particularly C-C bond oxidation catalysed by tailoring enzymes including cyclodipeptide oxidases. These flavin-dependent enzymes are underexplored due to their intricate three-dimensional arrangement involving multiple copies of two distinct small subunits, and mechanistic details underlying substrate selection and catalysis are lacking. Here, we determined the structure and mechanism of the cyclodipeptide oxidase from the halophile Nocardiopsis dassonvillei (NdasCDO), a component of the biosynthetic pathway for nocazine natural products. We demonstrated that NdasCDO forms filaments in solution, with a covalently bound flavin mononucleotide (FMN) cofactor at the interface between three distinct subunits. The enzyme exhibits promiscuity, processing various cyclic dipeptides as substrates in a distributive manner. The reaction is optimal at high pH and involves the formation of a radical intermediate. Pre-steady-state kinetics, a significant solvent kinetic isotope effect, and the absence of viscosity effects suggested that a step linked to FMN regeneration controlled the reaction rate. Our work elucidates the complex mechanistic and structural characteristics of this dehydrogenation reaction, positioning NdasCDO as a promising biocatalyst and expanding the FMN-dependent oxidase family to include enzyme filaments.

Isolation and Structural Determination of Cyclic Dipeptides Produced by Arthrobacter sp.

Isolation and Structural Determination of Cyclic Dipeptides Produced by Arthrobacter sp.

Enhancement of memory and reduction of amyloid plaques in alzheimer\'s disease mouse model using cyclic glycine-proline

Amyloid plaques and neurofibrillary tangles are two of the most important signs that can be used to diagnose Alzheimer's disease (AD), which is a neurodegenerative condition. Animal models, such as APP/PS1 mice, are extremely important for advancing our understanding of the factors that contribute to Alzheimer's disease and evaluating potential treatments. The purpose of this study is to investigate the effects of cyclic glycine-proline (cGP), a stable cyclic dipeptide that originates from glutamate, on spatial memory and the accumulation of amyloid plaque in mice with Alzheimer's disease and Parkinson's disease type 1.In order to evaluate the spatial memory of APP/PS1 mice, the Morris Water Maze was utilised after the mice had been administered cGP. To determine the amount of amyloid plaque in the brain, first the staining was done using thioflavin-S, then imaging was performed, and last the results were quantified. Treatment with cGP resulted in a considerable reduction in the quantity of amyloid plaque and an improvement in spatial memory in mice with APP/PS1 mutations. There was a decline in escape latency times, amyloid plaque numbers, and plaque covering percentages in the cortex and hippocampus.There is evidence to suggest that cGP may have therapeutic potential; in a rat model of Alzheimer's disease, it was found to improve cognitive performance and reduce amyloid pathology. The therapeutic potential of cGP in reducing AD pathology and cognitive impairment is demonstrated by these results.

Three New Dipeptide and Two New Polyketide Derivatives from the Mangrove-Derived Fungus Talaromyces sp.: Antioxidant Activity of Two Isolated Substances.

Five new metabolites, including three cyclic dipeptide derivatives (1-3) and two new polyketides (10-11), together with nine known ones (4-9 and 12-15), were isolated from the mangrove-sediments-derived fungus Talaromyces sp. SCSIO 41431. Their structures were determined using detailed NMR, MS spectroscopic analyses, and quantum chemical calculations. X-ray single-crystal diffraction analysis of 1 was described. Compounds 13-15 demonstrated activity against Staphylococcus aureus, with MIC values ranging from 25 to 50 µg/mL. Compound 9 showed activity against Escherichia coli, Streptococcus suis, and Erysipelothrix rhusiopathiae, with an MIC value of 100 µg/mL. In addition, compounds 1 and 12 showed DPPH radical scavenging activity, with the EC50 of 27.62 and 29.34 µg/mL, compared to the positive control (ascorbic acid, EC50, 12.74 µg/mL).

Novel Class of Ambipolar Columnar Liquid Crystals Based on Cyclic Dipeptide and Isatin Hybrids.

A new class of cyclic dipeptide-isatin hybrids was synthesized using 2,5-diketopiperazine and various isatin derivatives bearing flexible chains and extended aromatic rings in a double Knoevenagel condensation process. These new series demonstrate high solubility and good thermal stability with decomposition temperatures exceeding 370 °C, especially the molecular design with efficient space-filling (CI5 and CI6) stabilized columnar liquid crystalline phase. The hole and electron carrier mobility of the CI5 compound, measured using the space charge limited current (SCLC) technique, were found to be 9.46×10-4 cm2/V.s and 7.88×10-4 cm2/V.s respectively. The stabilization of columnar self-assembly and observation of ambipolar charge carrier mobility in cyclic dipeptide-isatin hybrids make them a promising class of self-assembling organic semiconductors.

Vibrational spectroscopic characterization, quantum chemical, molecular docking and molecular dynamics investigations of cyclo(L-phenylalanyl-L-proline), an anticancer agent

The molecular structure and spectral properties of cyclo(L-Phenylalanyl-L-Proline) dipeptide, which has several biological activities, were investigated. Firstly, conformational preference of the cyclo(L-Phenylalanyl-L-Proline) was searched and obtained lowest energy conformer of the cyclic dipeptide was then optimized using Density Functional Theory with wb97xd/6-311++G(d,p) level of theory. A detailed vibrational spectral analysis has been carried out and assignments of the fundamental modes have been proposed. The experimental vibrational wavenumbers of the investigated compound display good agreement with the computed values. The Frontier Molecular Orbitals, Molecular Electrostatic Potential and electronic transitions of the investigated compound were discussed. In addition, the 1H and 13C NMR chemical shifts of the cyclic dipeptide were calculated and the results were compared with the experimental values. Also, to evaluate the anticancer potential, molecular docking studies of cyclo(L-Phenylalanyl-L-Proline) within the ATP-binding sites of both wild type (EGFRWT; ID: 4HJO) and mutant (EGFRT790M; ID: 3W2O) Epidermal Growth Factor Receptor were performed. The results indicated that cyclo(Phe-Pro) has high binding affinities toward both EGFRWT (−6.6 kcal/mol) and EGFRT790M (−7.7 kcal/mol) receptors, thus, has good anticancer activity and also has potential to overcome drug resistance in therapy. Molecular dynamics simulations on cyclo(L-Phenylalanyl-L-Proline)-wild type complex were conducted through a 50-nanosecond timed to investigate the ligand-receptor interactions in more detail, and to determine the binding free energy accurately. The binding free energy of the cyclo(L-Phenylalanyl-L-Proline)-wild type complex was calculated to be −27.18 kcal/mol.

Increase in blood-transferable linear and cyclic dipeptides in human plasma following ingestion of elastin hydrolysate

Increase in blood-transferable linear and cyclic dipeptides in human plasma following ingestion of elastin hydrolysate

Characterization and Bioactive Metabolite Profiling of Streptomyces sp. Y009: A Mangrove-Derived Actinomycetia with Anticancer and Antioxidant Potential.

Microorganisms from poorly explored environments are promising sources for the development of novel drugs. In our continuous efforts to screen for mangrove actinomycetes that produce metabolites with potential pharmaceutical applications, Streptomyces sp. Y009 was isolated from mangrove sediments in Guangxi, China. The phenotypic, physiological, biochemical, and phylogenetic characteristics of this strain were investigated. Analysis of phylogenetic and 16S rRNA gene sequences showed that it had the highest sequence similarity to Streptomyces thermolilacinus NBRC 14274 (98.95%). Further, the Y009 extract exhibited antioxidant activity, as indicated by DPPH and superoxide dismutase assays. The extract showed broad-spectrum and potent anticancer potential against six human cancer cell lines, with IC50 values ranging from 5.61 to 72.15 μg/mL. Furthermore, the selectivity index (SI) demonstrated that the Y009 extract exhibited less toxicity toward normal cell lines in comparison to the lung cancer cell line (A549) and hepatoma cell line (HepG2). GC-MS analysis revealed that the extract contained some biologically important secondary metabolites, mainly cyclic dipeptides and esters, which might be responsible for the antioxidant and anticancer properties. 3-Isobutylhexahydropyrrolo[1,2-a]pyrazine-1,4-dione (28.32%) was the major chemical compound available in the extract. The effect on cancer cells was then confirmed using nuclear staining and in silico docking. This study suggests that further exploration of the bioactive compounds of the newly isolated strain may be a promising approach for the development of novel chemopreventive drugs.

Small cyclic dipeptide produced by Lactobacillus rhamnosus with anti-biofilm properties against Streptococcus mutans biofilm

Small cyclic dipeptide produced by Lactobacillus rhamnosus with anti-biofilm properties against Streptococcus mutans biofilm

Novel application of cyclo(-Phe-Pro) in mitigating aluminum toxicity through oxidative stress alleviation in wheat roots

Novel application of cyclo(-Phe-Pro) in mitigating aluminum toxicity through oxidative stress alleviation in wheat roots

Strategy For Solid-State Synthesis of the Cyclic Dipeptide from Phenylalanyl-Alanine and Alanyl-Phenylalanine

Strategy For Solid-State Synthesis of the Cyclic Dipeptide from Phenylalanyl-Alanine and Alanyl-Phenylalanine

Exploring the Frontier of Cyclic Dipeptides: A Bioinformatics Approach to Potential Therapeutic Applications in Schizophrenia.

Cyclic dipeptides (CDPs), known for their diverse biological activities, have potential therapeutic applications in mental and behavioral disorders (MBDs), particularly schizophrenia. This study explores the CDPs' therapeutic potential using bibliometric analysis, network pharmacology, molecular docking, and experimental verification, focusing on the interactions with the SIGMA1 receptor. A literature review over three decades utilizing the Web of Science Core Collection (WOSCC) was conducted to identify the emerging trends in CDPs research. A compound library was constructed from the PubChem database, and target prediction using SwissTargetPrediction revealed 800 potential protein targets. A compound-target network highlighted the key interactions with kinases, G protein-coupled receptors, and chromatin-modifying enzymes. Enrichment analysis revealed significant associations with schizophrenia and other MBDs. Schizophrenia-related targets among the potential protein targets were identified using the GEO database. Molecular docking results showed interactions of MC4R, OPRK1, SIGMA1, and CDK5R1 with various CDPs compounds, with SIGMA1 being especially noteworthy. Most CDPs exhibited lower binding energies than the control compounds NE-100 and duloxetine. Experimental validation demonstrated that CDPs such as Cyclo(Ala-Gln), Cyclo(Ala-His), and Cyclo(Val-Gly) exhibited IC50 values of 13.4, 19.4, and 11.5 μM, respectively, against SIGMA1, indicating biological activity. Our findings underscore their potential as therapeutic agents for schizophrenia, highlighting the need for further modifications to enhance specificity and efficacy. This work paves the way for future investigations into CDPs, contributing to developing targeted treatments for schizophrenia and related mental health disorders.

Unusual Cross-Conjugation in Cyclic Dipeptide-Based Building Blocks for Donor-Acceptor Semiconducting Conjugated Polymers.

Cross conjugation, though prevalent in many organic compounds, is typically considered less effective for electron delocalization compared to linear conjugation. Consequently, it is rarely used as the backbone structure for semiconducting conjugated polymers. In this study, we designed and synthesized a novel building block, TIDP, which features a central cyclic dipeptide with cross conjugation characteristics. Strong intramolecular hydrogen bonding interactions confer TIDP with a highly rigid and coplanar conformation. Importantly, theoretical calculations reveal that π electrons are well delocalized across the entire structure, despite its low aromaticity. Conjugated polymers incorporating TIDP exhibit high charge carrier mobilities, demonstrating the effective π electrons delocalization of this innovative building block. Our findings show that with rational design, cross conjugation can achieve effective π electrons delocalization, providing a valuable approach for developing high-performance conjugated polymers for organic electronic materials.

Unusual Cross‐Conjugation in Cyclic Dipeptide‐Based Building Blocks for Donor–Acceptor Semiconducting Conjugated Polymers

AbstractCross conjugation, though prevalent in many organic compounds, is typically considered less effective for electron delocalization compared to linear conjugation. Consequently, it is rarely used as the backbone structure for semiconducting conjugated polymers. In this study, we designed and synthesized a novel building block, TIDP, which features a central cyclic dipeptide with cross conjugation characteristics. Strong intramolecular hydrogen bonding interactions confer TIDP with a highly rigid and coplanar conformation. Importantly, theoretical calculations reveal that π electrons are well delocalized across the entire structure, despite its low aromaticity. Conjugated polymers incorporating TIDP exhibit high charge carrier mobilities, demonstrating the effective π electrons delocalization of this innovative building block. Our findings show that with rational design, cross conjugation can achieve effective π electrons delocalization, providing a valuable approach for developing high‐performance conjugated polymers for organic electronic materials.

Photoprotective Effects of Yeast Pulcherrimin.

Sunscreen products can protect the skin against the harmful effects of UV radiation, including reddening, aging, and cancer. The aim of this research was to evaluate the photoprotective effects of yeast pulcherrimin, an iron-chelating dipeptide. We first investigated the cytotoxicity of pulcherrimin produced by Metschnikowia pulcherrima yeast on the human keratinocyte HaCaT cell line, using the PrestoBlue assay. We assessed the ability of pulcherrimin to induce DNA repair after the exposure of HaCaT cells to oxidative stress. We also evaluated its protective activity against UVC radiation. The sun protective factor (SPF) was calculated using the Mansur equation. The UVA/UVB ratio values for pure pulcherrimin were evaluated using the Boots Star Rating system. The critical wavelength was determined by calculating the integrated optical density curve area. Based on the results, pulcherrimin shows strong cytoprotective effects through antioxidant and photoprotective activities on the HaCaT cell line. The calculated SPFs were 20 and 15 at pH = 7 and pH = 10, respectively. The critical wavelength above 370 nm and the UVA/UVB ratio R > 1 suggest that yeast pulcherrimin-a cyclic dipeptide containing iron-may be considered a promising photoprotective agent.

Evaluation of the electrochemical response of aromatic peptides for biodetection of dopamine

Evaluation of the electrochemical response of aromatic peptides for biodetection of dopamine