Cyclic Heptapeptide Research Articles

An antimicrobial peptide specifically active against Listeria monocytogenes is secreted by Bacillus pumilus SF214

BackgroundMembers of the Bacillus genus produce a large variety of antimicrobial peptides including linear or cyclic lipopeptides and thiopeptides, that often have a broad spectrum of action against Gram-positive and Gram-negative bacteria. We have recently reported that SF214, a marine isolated strain of Bacillus pumilus, produces two different antimicrobials specifically active against either Staphylococcus aureus or Listeria monocytogenes. The anti-Staphylococcus molecule has been previously characterized as a pumilacidin, a nonribosomally synthesized lipopetide composed of a mixture of cyclic heptapeptides linked to fatty acids of variable length.ResultsOur analysis on the anti-Listeria molecule of B. pumilus SF214 indicated that it is a peptide slightly smaller than 10 kDa, produced during the exponential phase of growth, stable at a wide range of pH conditions and resistant to various chemical treatments. The peptide showed a lytic activity against growing but not resting cells of Listeria monocytogenes and appeared extremely specific being inactive also against L. innocua, a close relative of L. monocytogenes.ConclusionsThese findings indicate that the B. pumilus peptide is unusual with respect to other antimicrobials both for its time of synthesis and secretion and for its strict specificity against L. monocytogenes. Such specificity, together with its stability, propose this new antimicrobial as a tool for potential biotechnological applications in the fight against the dangerous food-borne pathogen L. monocytogenes.

Preclinical assessment of Alzheimer's disease using novel designed 99mTc‐labeled RGD‐based pro‐apoptotic cyclic peptide as a promising SPECT agent

The increased prevalence of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and glioma results in increased risks to abolish the healthy life. This is because of inducing alternation causes into the intracellular compartment as well as noncell compartments. Therefore, herein, a simple and facile radiosynthesis strategy was employed for the development of a novel 99mTc (t1/2 = 6 h, Er = 140 keV) labeled diethylenetriamine pentaacetic acid (DTPA) conjugated cyclic heptapeptide (99mTc‐DTPA‐c[RGDKLAK]; cPT). The radiotracer was characterized using various analytical techniques to evaluate the identity, radiolabeling, biocompatibility, in vitro stability, and amenability for preclinical use. The biological specificity and efficacy of the radiolabeled cyclic peptide analog were confirmed by in vivo biodistribution and single‐photon emission computed tomography (SPECT) studies in Alzheimer disease (AD)‐induced animal models. The results demonstrated that 99mTc(CO)3‐DTPA‐cPT showed high radioactivity concentration at the site of αvβ3, α5β1‐integrins expressing brain regions while decreasing radioactivity levels in kidneys and increasing urinary bladder over the period of 3 h suggested the renal clearance route of the radiotracer. The diagnostic outcomes obtained from planar SPECT study are consistent with that of the biodistribution study with a target‐to‐nontarget ratio (T/NT = 28.47 ± 2.53) at 3‐h postinjection. The results are surprisingly supportive to our hypothesis that the small cyclic peptide‐based radiotracer is well‐oriented towards targeted drug delivery and envisaged that our proposed radiotracer 99mTc(CO)3‐DTPA‐cPT has potential diagnostic applications for Alzheimer's disease as a novel SPECT agent.

Synthesis of the cyclic heptapeptide core of callipeltin A

Macrolactonisation of a suitable heptapeptide precursor provides the cyclic depsipeptide core of callipeltin A in excellent yield.

Rapid Detection and Quantification of Microcystins in Surface Water by an Impedimetric Biosensor

Microcystins are a group of toxic cyclic heptapeptides produced by common cyanobacteria. The accumulation of microcystins in water reservoirs is an emerging worldwide problem. Exposure to microcystins is mainly associated with hepatotoxicity and carcinogenesis and leads to both acute and chronic damages. Microcystin-LR (MC-LR), the most common microcystin, accounts for most reported poisonings and is considered an imminent threat to human and animal health. Consequently, stringent regulation has recently been imposed by the World Health Organization (WHO), limiting the allowed MC-LR concentration in drinking water to <1 μg/L and a maximal daily intake of 0.04 μg/kg body weight. Current methods for MC-LR detection generally rely on chromatography coupled with mass spectrometry requiring bulky and expensive equipment, highly trained personnel, and labor-intensive preparation steps. Therefore, there is an urgent need for an affordable, on-site diagnostic tool providing a rapid quantitative determination of MC-LR in surface waters.We have developed an electrochemical biosensor for MC-LR detection based on the transduction of bimolecular binding into an electrochemical signal. Specific antibodies were integrated with a biochip and measurement platform, applied in the detection of MC-LR by electrochemical impedance spectroscopy. Using the miniaturized platform, quantitative detection of MC-LR was feasible, exhibiting a dynamic range of five logarithmic concentrations and a limit of detection of 3 ng/L (3 part-per-trillion). This LOD is superior to currently employed solid-phase immunoassays. Furthermore, specific detection of MC-LR from models of cyanobacteria-contaminated water was demonstrated by the developed biosensor. Based on our findings, we anticipate that in the near future electrochemical biosensors would be an essential tool in water monitoring and environmental diagnostics. Figure 1

Hybridization of tumor homing and mitochondria-targeting peptide domains to design novel dual-imaging self-assembled peptide nanoparticles for theranostic applications.

A novel hybridized dual-targeting peptide-based nanoprobe was successfully designed by using the cyclic heptapeptide. This peptide has Arg-Gly-Asp-Lys-Leu-Ala-Lys sequence, in which the RGD homing motif and KALK mitochondria-targeting motif were linked via amide bond. The designed peptide probe was further modified through covalent linkage to induce dual-imaging functionality, and self-assembled to form spherical nanoparticles. The novel Cy5.5-SAPD-99mTc nanoparticles were tested for in vitro cytotoxicity, cellular uptake, and apoptosis-inducing functionalities. The cellular internalization, enhanced cytotoxicity and selective receptor binding capabilities against U87MG cells, excellent dual-imaging potential, improved apoptosis-inducing feature by damaging mitochondria, and in vivo preclinical investigations suggested that our newly designed novel hybridized peptide-based dual-imaging nanoparticles may serve as an admirable theranostic probe to treat brain tumor glioblastoma multiforme. This study describes the development of dual-targeting self-assembled peptide nanoparticles followed by modifications using NIRF dye and radiolabeled with 99mTc for dual-imaging and enhanced therapeutic efficacy against brain tumor.

A Brief Review of the Structure, Cytotoxicity, Synthesis, and Biodegradation of Microcystins

Harmful cyanobacterial blooms pose an environmental health hazard due to the release of water-soluble cyanotoxins. One of the most prevalent cyanotoxins in nature is microcystins (MCs), a class of cyclic heptapeptide hepatotoxins, and they are produced by several common cyanobacteria in aquatic environments. Once released from cyanobacterial cells, MCs are subjected to physical chemical and biological transformations in natural environments. MCs can also be taken up and accumulated in aquatic organisms and their grazers/predators and induce toxic effects in several organisms, including humans. This brief review aimed to summarize our current understanding on the chemical structure, exposure pathway, cytotoxicity, biosynthesis, and environmental transformation of microcystins.

Identifying the Cellular Target of Cordyheptapeptide A and Synthetic Derivatives.

Cordyheptapeptide A is a lipophilic cyclic peptide from the prized Cordyceps fungal genus that shows potent cytotoxicity in multiple cancer cell lines. To better understand the bioactivity and physicochemical properties of cordyheptapeptide A with the ultimate goal of identifying its cellular target, we developed a solid-phase synthesis of this multiply N-methylated cyclic heptapeptide which enabled rapid access to both side chain- and backbone-modified derivatives. Removal of one of the backbone amide N-methyl (N-Me) groups maintained bioactivity, while membrane permeability was also preserved due to the formation of a new intramolecular hydrogen bond in a low dielectric solvent. Based on its cytotoxicity profile in the NCI-60 cell line panel, as well as its phenotype in a microscopy-based cytological assay, we hypothesized that cordyheptapeptide was acting on cells as a protein synthesis inhibitor. Further studies revealed the molecular target of cordyheptapeptide A to be the eukaryotic translation elongation factor 1A (eEF1A), a target shared by other lipophilic cyclic peptide natural products. This work offers a strategy to study and improve cyclic peptide natural products while highlighting the ability of these lipophilic compounds to effectively inhibit intracellular disease targets.

Cover Feature: Peptide Head‐to‐Tail Cyclization: A “Molecular Claw” Approach (22/2021)

The Cover Feature shows a schematic impression of the “molecular claw” approach that enables an effective head (C-terminus)-to-tail (N-terminus) cyclization of peptides. Tag-assisted liquid phase peptide synthesis in combination with a backbone amide linker strategy is generally applicable to the head-to-tail cyclization, leading to the efficient synthesis of the cyclic heptapeptide stellarin E. The key for successful cyclization is found to be the tagging position that enables the peptide to be grabbed at the center as in a claw-like machine. More information can be found in the Communication by K. Chiba et al.

The HGR motif is the antiangiogenic determinant of vasoinhibin: implications for a therapeutic orally active oligopeptide

The hormone prolactin acquires antiangiogenic and antivasopermeability properties after undergoing proteolytic cleavage to vasoinhibin, an endogenous prolactin fragment of 123 or more amino acids that inhibits the action of multiple proangiogenic factors. Preclinical and clinical evidence supports the therapeutic potential of vasoinhibin against angiogenesis-related diseases including diabetic retinopathy, peripartum cardiomyopathy, rheumatoid arthritis, and cancer. However, the use of vasoinhibin in the clinic has been limited by difficulties in its production. Here, we removed this barrier to using vasoinhibin as a therapeutic agent by showing that a short linear motif of just three residues (His46-Gly47-Arg48) (HGR) is the functional determinant of vasoinhibin. The HGR motif is conserved throughout evolution, its mutation led to vasoinhibin loss of function, and oligopeptides containing this sequence inhibited angiogenesis and vasopermeability with the same potency as whole vasoinhibin. Furthermore, the oral administration of an optimized cyclic retro-inverse vasoinhibin heptapeptide containing HGR inhibited melanoma tumor growth and vascularization in mice and exhibited equal or higher antiangiogenic potency than other antiangiogenic molecules currently used as anti-cancer drugs in the clinic. Finally, by unveiling the mechanism that obscures the HGR motif in prolactin, we anticipate the development of vasoinhibin-specific antibodies to solve the on-going challenge of measuring endogenous vasoinhibin levels for diagnostic and interventional purposes, the design of vasoinhibin antagonists for managing insufficient angiogenesis, and the identification of putative therapeutic proteins containing HGR.

Lingaoamide, a cyclic heptapeptide from a Chinese freshwater cyanobacterium Oscillatoria sp.

Lingaoamide (1), a new cyclic heptapeptide natural product, was isolated from a freshwater Oscillatoria cyanobacterium. The producing organism was collected in Chinese water spinach paddy farm fields in Lingao County, Hainan, China. The structure of 1 was determined by conventional mass spectrometry, NMR spectroscopy, and chemical degradation studies. Lingaoamide concentration-dependently up-regulates the biogenesis of pro-pathogenic melanin pigments (melanogenesis) in the rice blast fungus, Magnaporthe grisea, when tested in vitro. This molecule also exhibits weak in vitro inhibition (MIC 32 μg/mL) of Gram-negative Pseudomonas aeruginosa and Gram-positive Bacillus pumilus, and does not appear to impact plant growth or immune response in vivo using the model organism, Arabidopsis thaliana.

Genetic engineering of the precursor supply pathway for the overproduction of the nC14-surfactin isoform with promising MEOR applications

BackgroundSurfactin, a representative biosurfactant of lipopeptide mainly produced by Bacillus subtilis, consists of a cyclic heptapeptide linked to a β-hydroxy fatty acid chain. The functional activity of surfactin is closely related to the length and isomerism of the fatty acid chain.ResultsIn this study, the fatty acid precursor supply pathway in Bacillus subtilis 168 for surfactin production was strengthened through two steps. Firstly, pathways competing for the precursors were eliminated with inactivation of pps and pks. Secondly, the plant medium-chain acyl-carrier protein (ACP) thioesterase (BTE) from Umbellularia californica was overexpressed. As a result, the surfactin titer after 24 h of cultivation improved by 34%, and the production rate increased from 0.112 to 0.177 g/L/h. The isoforms identified by RP-HPLC and GC–MS showed that the proportion of nC14-surfactin increased 6.4 times compared to the control strain. A comparison of further properties revealed that the product with more nC14-surfactin had higher surface activity and better performance in oil-washing. Finally, the product with more nC14-surfactin isoform had a higher hydrocarbon-emulsification index, and it increased the water-wettability of the oil-saturated silicate surface.ConclusionThe obtained results identified that enhancing the supply of fatty acid precursor is very essential for the synthesis of surfactin. At the same time, this study also proved that thioesterase BTE can promote the production of nC14-surfactin and experimentally demonstrated its higher surface activity and better performance in oil-washing. These results are of great significance for the MEOR application of surfactin.Graphic abstract

Molecular Dynamics Study of Surfactin Interaction with Lipid Bilayer Membranes

Background: Surfactin is a cyclic heptapeptide that is closed by a β-hydroxy fatty acid chain. This potent biosurfactant is produced by different Bacillus subtilis strains. This lipopeptide has numerous attractive biological activities, including antibacterial, antiviral, antimycoplasma, hemolytic, and other different and powerful surface and interface activities. Methods: Understanding how surfactin binds to different membranes and its mechanism of action can help us modify and optimize its structure to improve the potential efficacy of this lipopeptide in the future. For this purpose, we studied the interaction of this lipopeptide with two types of lipid bilayer models, including palmitoyl-oleoyl-glycero- phosphocholine (POPC) and palmitoyl-oleoyl-phosphtidylglycerol (POPG) as the prokaryotic and eukaryotic membrane models, respectively. Results: The obtained data have shown that the tendency of surfactin for these membranes is different. According to the analysis, this molecule binds to both membranes peripherally, and its interaction with the negative membrane is also more potent compared to the zwitterionic membrane. Moreover, we found that surfactin destabilized POPG more than POPC. This suggests that surfactin may act by modifying the membrane’s bulk physical properties. Conclusions: As a final point, this study has shown that surfactin has different behaviors in the eukaryotic and prokaryotic cell membranes and can modify and amplify its action in order to use it for antibacterial drugs.

Cucurbituril Ameliorates Liver Damage Induced by Microcystis aeruginosa in a Mouse Model.

Microcystis aeruginosa is a cyanobacterium that produces a variety of cyclic heptapeptide toxins in freshwater. The protective effects of the macromolecular container cucurbit[7]uril (CB7) were evaluated using mouse models of cyanotoxin-induced liver damage. Biochemical analysis of liver function was performed to gauge the extent of liver damage after exposure to cyanobacterial crude extract [CCE; LD50 = 35 mg/kg body weight; intraperitoneal (i.p.)] in the absence or presence of CB7 (35 mg/kg body weight, i.p.). CCE injection resulted in liver enlargement, potentiated the activities of alanine aminotransferase (ALT) and glutathione S-transferase (GST), increased lipid peroxidation (LPO), and reduced protein phosphatase 1 (PP1) activity. CCE-induced liver enlargement, ALT and GST activities, and LPO were significantly reduced when CB7 was coadministered. Moreover, the CCE-induced decline of PP1 activity was also ameliorated in the presence of CB7. Treatment with CB7 alone did not affect liver function, which exhibited a dose tolerance of 100 mg/kg body wt. Overall, our results illustrated that the addition of CB7 significantly reduced CCE-induced hepatotoxicity (P < 0.05).

Oxidative stress induced in rice suspension cells exposed to microcystin-LR at environmentally relevant concentrations.

Microcystins (MCs) are cyclic heptapeptide hepatotoxins that are highly soluble in water and can be transferred to farmland through irrigation with potentially substantial effects on crops, especially rice. In order to investigate the possible negative effects of microcystin-LR (MC-LR) on rice, the oxidative stress induced in rice suspension cells exposed to MC-LR at environmentally relevant concentrations (0.05, 0.5, 5.0, and 50.0 μg·L-1) was investigated. Results showed that the exposure to MC-LR at 0.5-50.0 μg·L-1 resulted in a significant decline in viability of rice suspension cells and an increase in malondialdehyde (MDA) contents. In the 50.0-μg·L-1 MC-LR treatment group, the content of MDA was as much as 5.39 times that of the control group after 6 days of exposure. The excess MDA production indicated that MC-LR exposure has caused lipid peroxidation damage in rice cells, whereas these negative effects could be recovered over time when suspension cells were exposed to low concentration of MC-LR (0.05 μg·L-1). When exposed to MC-LR for 3 days, the O2- content in all treatment groups increased significantly compared with the control group. Additionally, the antioxidant system of rice suspension cells initiated a positive stress response to MC-LR exposure. Indeed, peroxidase (POD) played an active role in the removal of reactive oxygen species (ROS) in rice suspension cells during the early period of exposure, while total superoxide dismutase (T-SOD) was induced after 6 days. Similarly, after 6 days of exposure, the anti-superoxide anion free radical activity (ASAFR), glutathione (GSH), and glutathione-S transferase (GST) in rice suspension cells were higher than that in the control group. These results provided a comprehensive understanding of the exposure time- and dose-dependent oxidative stress induced by the environmentally relevant concentrations of MC-LR in rice suspension cells.

Ectyoplasin, a novel cytotoxic cyclic peptide from Ectyoplasia ferox sponge

A new cyclic heptapeptide, ectyoplasin (1), was isolated from a methanol extract of the sponge Ectyoplasia ferox. The planar structure of 1, cyclo(-Leu1-Asn2-Ala3-Val4-Thr5-Pro6-Gly7-), was determined by one and two-dimensional NMR spectroscopy and high-resolution tandem mass spectrometry. Its absolute stereochemistry was solved by Marfey’s method. The in vitro assays show that ectyoplasin (1) possess significant cytotoxic activity (2.9 − 23.5 µM) against the cell lines, DU-145 (human prostate cancer), Jurkat (human T-cell acute leukaemia), MM144 (human multiple myeloma), HeLa (human cervical carcinoma) and CADO-ES1 (human Ewing’s sarcoma). The DU-145 cell line showed apoptotic cell death in response to ectyoplasin (1) treatment.

Recapitulating the Binding Affinity of Nrf2 for KEAP1 in a Cyclic Heptapeptide, Guided by NMR, X-ray Crystallography, and Machine Learning.

Macrocycles, including macrocyclic peptides, have shown promise for targeting challenging protein-protein interactions (PPIs). One PPI of high interest is between Kelch-like ECH-Associated Protein-1 (KEAP1) and Nuclear Factor (Erythroid-derived 2)-like 2 (Nrf2). Guided by X-ray crystallography, NMR, modeling, and machine learning, we show that the full 20 nM binding affinity of Nrf2 for KEAP1 can be recapitulated in a cyclic 7-mer peptide, c[(D)-β-homoAla-DPETGE]. This compound was identified from the Nrf2-derived linear peptide GDEETGE (KD = 4.3 μM) solely by optimizing the conformation of the cyclic compound, without changing any KEAP1 interacting residue. X-ray crystal structures were determined for each linear and cyclic peptide variant bound to KEAP1. Despite large variations in affinity, no obvious differences in the conformation of the peptide binding residues or in the interactions they made with KEAP1 were observed. However, analysis of the X-ray structures by machine learning showed that locations of strain in the bound ligand could be identified through patterns of subangstrom distortions from the geometry observed for unstrained linear peptides. We show that optimizing the cyclic peptide affinity was driven partly through conformational preorganization associated with a proline substitution at position 78 and with the geometry of the noninteracting residue Asp77 and partly by decreasing strain in the ETGE motif itself. This approach may have utility in dissecting the trade-off between conformational preorganization and strain in other ligand-receptor systems. We also identify a pair of conserved hydrophobic residues flanking the core DxETGE motif which play a conformational role in facilitating the high-affinity binding of Nrf2 to KEAP1.

Biosynthetic Interrogation of Soil Metagenomes Reveals Metamarin, an Uncommon Cyclomarin Congener with Activity against Mycobacterium tuberculosis.

Tuberculosis (TB) remains one of the deadliest infectious diseases. Unfortunately, the development of antibiotic resistance threatens our current therapeutic arsenal, which has necessitated the discovery and development of novel antibiotics against drug-resistant Mycobacterium tuberculosis (Mtb). Cyclomarin A and rufomycin I are structurally related cyclic heptapeptides assembled by nonribosomal peptide synthetases (NRPSs), which show potent anti-Mtb activity with a new cellular target, the caseinolytic protein ClpC1. An NRPS adenylation domain survey using DNA extracted from ∼2000 ecologically diverse soils found low cyclomarin/rufomycin biosynthetic diversity. In this survey, a family of cyclomarin/rufomycin-like biosynthetic gene clusters (BGC) that encode metamarin, an uncommon cyclomarin congener with potent activity against both Mtb H37Rv and multidrug-resistant Mtb clinical isolates was identified. Metamarin effectively inhibits Mtb growth in murine macrophages and increases the activities of ClpC1 ATPase and the associated ClpC1/P1/P2 protease complex, thus causing cell death by uncontrolled protein degradation.

The mechanisms of mitochondrial dysfunction and glucose intake decrease induced by Microcystin-LR in ovarian granulosa cells

Microcystin-LR (MC-LR) is a cyclic heptapeptide; it is an intracellular toxin released by cyanobacteria that exhibits strong reproductive toxicity. Previous studies have demonstrated that MC-LR induces oxidative stress in granulosa cells by damaging the mitochondria, which eventually leads to follicle atresia and female subfertility. In the present study, granulosa cells were exposed to 0, 0.01, 0.1 and 1 μM MC-LR. After 24 h, we observed changes in mitochondrial cristae morphology and dynamics by analyzing the results of mitochondrial transmission electron microscopy and detecting the expression of DRP1. We also evaluated glucose intake using biochemical assays and expression of glucose transport related proteins. MC-LR exposure resulted in mitochondrial fragmentation and glucose intake decrease in granulosa cells, as shown by increasing mitochondrial fission via dynamin-related protein 1 (DRP1) upregulation and decreasing glucose transporter 1 and 4 (GLUT1 and GLUT4). Furthermore, the expression levels of forkhead box protein M1 (FOXM1) significantly increased due to the overproduction of reactive oxygen species (ROS) after MC-LR exposure. Our results proved that MC-LR exposure causes mitochondrial fragmentation and glucose intake decrease in granulosa cells, which provides new insights to study the molecular mechanism of female reproductive toxicity induced by MC-LR.

Multifunctional self-assembled peptide nanoparticles for multimodal imaging-guided enhanced theranostic applications against glioblastoma multiforme.

The synthesis of self-assembled peptide nanoparticles using a facile one-pot synthesis approach is gaining increasing attention, allowing therapy in combination with diagnosis. Their drawback is limited diagnostic potential, which can be improved after necessary modifications and efficacious functionalization. Herein, a cyclic heptapeptide having the Arg-Gly-Asp-Lys-Leu-Ala-Lys sequence was modified by conjugation of the ε-amino group of the terminal lysine residue with diethylenetriamine pentaacetic acid (DTPA) as a bifunctional chelating agent (BFC) for radiolabeling with a γ-emitting radionuclide (99mTc, half-life 6.01 h; energy 140 keV). Further, the free amino group of the middle lysine residue was successfully conjugated with near-infrared fluorescence (NIRF) dye Cyanine5.5 N-succinimidyl ester (Ex/Em = 670/701 nm) by a co-assembly method to form newly designed novel NIRF dye conjugated self-assembled peptide–DTPA (Cy5.5@SAPD) nanoparticles. The fluorescent nanoparticle formation was confirmed by using a fluorescence spectrophotometer (Ex/Em = 650/701 nm), and the transmission electron microscope (TEM) images showed a size of ∼ 40 nm with a lattice fringe distance of 0.294 nm. Cytotoxicity and confocal laser scanning microscopy (CLSM) studies showed that these nanoparticles possess a high affinity for the αvβ3-integrin receptor overexpressed on brain tumor glioblastoma with an EC50 = 20 μM. Moreover, these nanoparticles were observed to have potential to internalize into U87MG cells more prominently than HEK-293 cancer cells and induce apoptosis. The apoptosis assay showed 79.5% apoptotic cells after 24 h treatment of Cy5.5@SAPD nanoparticles. Additionally, these nanoparticles were also radiolabeled with 99mTc for the single photon emission computed tomography (SPECT) imaging study in tumor-bearing female Balb/c mice. The excellent imaging feature of Cy5.5@SAPD-99mTc nanoparticles as a multimodal (SPECT/NIRF) diagnostic probe, as well as noteworthy therapeutic potential was observed. The results suggested that our newly designed novel dual-targeting dual-imaging nanoparticles may serve as an admirable theranostic probe to treat brain tumor glioblastoma multiforme.

Unguisin G, a new kynurenine-containing cyclic heptapeptide from the sponge-associated fungus Aspergillus candidus NF2412

One new cyclic heptapeptide containing non-proteinogenic amino acid residues kynurenine and γ-aminobutyric acid, named unguisin G, as well as three known congeners unguisins A, E and F, were isolated from a sponge-derived fungus Aspergillus candidus NF2412. The structures were elucidated by comprehensive spectroscopic analyses of HRESIMS and NMR data. The absolute configuration of amino acid residues of 1 was determined by advanced Marfey’s method. All compounds were evaluated on antimicrobial activities against nine pathogens by the agar diffusion method.