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(A) Molecular docking of spinochromes into a potential binding site of the 3-OS HS tetrasaccharide and the HSV-1 gD membrane glycoprotein. The electrostatic potential of the gD molecular surface was calculated using the MOE 2019.01 program. The spinochrome structures are shown as sticks. (B) 2D diagram of contacts of EchA, EamA, and EamB protomers with gD.
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Herpes simplex virus type 1 (HSV-1) is one of the most prevalent pathogens worldwide requiring the search for new candidates for the creation of antiherpetic drugs. The ability of sea urchin spinochromes-echinochrome A (EchA) and its aminated analogues, echinamines A (EamA) and B (EamB)-to inhibit different stages of HSV-1 infection in Vero cells a...
Citations
... Besides collagen, sea urchins possess peculiar secondary metabolites known as polyhydroxynaphthoquinones (PHNQs), which exhibit potent antioxidant properties [14][15][16][17] . In addition to their radical scavenging ability, PHNQs showed other relevant and potentially exploitable biological activities, such as immune modulation 14,15 , antimicrobial 18,19 , antiviral 20 and cardioprotective 21 activities. Several PHNQs have been identified till now, from different sea urchin species 14,[22][23][24] the most common and best studied being Echinochrome A and Spinochromes A-E 25 . ...
Chronic wounds and skin ulcers pose significant challenges to healthcare systems globally, necessitating innovative approaches to expedite healing processes. Biomaterial-based therapies have emerged as promising solutions for tissue regeneration. This study focuses on valorization of sea urchin waste towards the development and characterization of collagen-based scaffolds added with polyhydroxynaphthoquinones (PHNQs) antioxidants, successfully incorporated into biomaterials at optimal ratio, enhancing scaffold stability and integrity. Mechanical properties, water uptake, and degradation kinetics of the composite scaffolds were evaluated and compared with controls. Results indicate that composite scaffolds exhibit superior mechanical stability and slower degradation rates, attributed to strong interactions between collagen and PHNQs. This aspect was explored also through in silico investigations by means of Tight Binding Molecular Dynamics methods. It has been found that a covalent bond forms between the selected collagen representative and one PHNQ. Furthermore, the antioxidant activity of PHNQs was retained in the composite scaffolds, providing additional therapeutic benefits. Overall, these findings underscore the potential of collagen-based composite scaffolds as advanced wound healing therapeutics, combining regenerative properties with antioxidant effects for improved clinical outcomes.
... Ech A has exhibited in vitro and in vivo bioactivity in multiple tissues including kidney (Cui et al., 2022), skin (Choi et al., 2022;Kim et al., 2023;Seol et al., 2021;Yun et al., 2021), heart (Artyukov et al., 2020;Jeong, Kim, Song, Lee, et al., 2014;Kim et al., 2015;Song et al., 2022;Tang et al., 2023), bone (Hou et al., 2020), lung (Lebed'ko et al., 2015;Seo et al., 2015) and eyes (Lennikov et al., 2014). These results may help explain the therapeutic efficacy of Ech A, perhaps via the antioxidant, anti-inflammatory and metal-chelating activities, against several common ailments and diseases (e.g., diabetes (Mohamed et al., 2016;Pham et al., 2023), ischemia/stroke (Kim et al., 2019;Sedova et al., 2015), viral infections (Fedoreyev et al., 2018;Mishchenko et al., 2020), bacterial infections (Sadek et al., 2021), inflammation Rubilar et al., 2021;Sadek et al., 2021), cancer (Lazarev et al., 2016;Mohamed, 2021) and neurodegenerative diseases (Ekimova et al., 2018;Lee, Pronto, et al., 2014)). As only genes involved in these bioactivities have been investigated (e.g., GSH and SOD genes to explain antioxidant bioactivity; ERK and p53 genes to explain cell survival signaling bioactivity), The genes and pathways mediating these bioactivities are not fully understood. ...
Evechinus chloroticus (commonly known as kina) is a sea urchin species endemic to New Zealand. Its roe is a culinary delicacy to the indigenous Māori and a globally exported food product. Echinochrome A (Ech A) is a bioactive compound isolated from the waste product of kina shells and spines; however, the molecular mechanisms of Ech A bioactivity are not well understood, partly due to Ech A never being studied using unbiased genome‐wide analysis. To explore the high‐value pharmaceutical potential of kina food waste, we obtained unbiased functional genomic and proteomic profiles of yeast cells treated with Echinochrome A. Abundance was measured for 4100 proteins every 30 min for four hours using fluorescent microscopy, resulting in the identification of 92 proteins with significant alterations in protein abundance caused by Ech A treatment that were over‐represented with specific changes in DNA replication, repair and RNA binding after 30 min, followed by specific changes in the metabolism of metal ions (specifically iron and copper) from 60–240 min. Further analysis indicated that Ech A chelated iron, and that iron supplementation negated the growth inhibition caused by Ech A. Via a growth‐based genome‐wide analysis of 4800 gene deletion strains, 20 gene deletion strains were sensitive to Ech A in an iron‐dependent manner. These genes were over‐represented in the cellular response to oxidative stress, suggesting that Ech A suppressed growth inhibition caused by oxidative stress. Unexpectedly, genes integral to cardiolipin and inositol phosphate biosynthesis were required for Ech A bioactivity. Overall, these results identify genes, proteins, and cellular processes mediating the bioactivity of Ech A. Moreover, we demonstrate unbiased genomic and proteomic methodology that will be useful for characterizing bioactive compounds in food and food waste.
... Moreover, due to the diverse biological activities of their secondary metabolites, echinoderms have become the great potential sources of antiviral drugs. Mishchenko et al. reported that the sea urchin derived echinochrome analogues EAMA and EAMB can significantly reduce the plaque formation of HSV-1 in Vero cells, and they may directly bind to virus gD protein to compete for the binding sites between the protein and cell receptors, thereby preventing virus adsorption on cells (Mishchenko et al., 2020). In addition, two new triterpenoid glycosides A and B isolated from sea cucumber showed antiviral activities against HSV-1 at concentrations below 10 ug/mL (Maier et al., 2001). ...
... Besides, l-carrageenan from Gigartina skottsbergii can firmly bind to HSV receptors in order to block the attachment of HSV to the host cell surfaces (Carlucci et al., 1997;Carlucci et al., 1999b). Moreover, spinochromes derived from sea urchins were reported to be able to directly bind to HSV gD protein to compete for the binding site of this protein with cell receptors (3-OS HS and Nectin-1), thereby preventing virus adsorption on cell surface (Mishchenko et al., 2020). In addition, the sea cucumber derived Octadecanoic acid ether ester exhibited the anti-HSV action mainly through interference with the attachment of HSV to host cell receptors (Keshavarz et al., 2021). ...
... Enhancing immune system (Marino-Merlo et al., 2017) Peptide A-3302-B Inhibition of replication (Sureram et al., 2022) Tunicates Ethanol extract Inhibition of replication (ZP et al., 2015) Echinoderms Sea urchin spinochromes Inhibition of adsorption (Mishchenko et al., 2020) Octadecanoic acid ether ester (Sea cucumber) Inhibition of adsorption (Keshavarz et al., 2021) Molluscs Abalone hemocyanin Inhibition of entry (Farshadpour et al., 2014) localization of gB in Golgi apparatus and endoplasmic reticulum (Wang Z. et al., 2020). ...
Herpes simplex virus (HSV) is the most widely prevalent herpes virus worldwide, and the herpetic encephalitis and genital herpes caused by HSV infection have caused serious harm to human health all over the world. Although many anti-HSV drugs such as nucleoside analogues have been ap-proved for clinical use during the past few decades, important issues, such as drug resistance, toxicity, and high cost of drugs, remain unresolved. Recently, the studies on the anti-HSV activities of marine natural products, such as marine polysaccharides, marine peptides and microbial secondary metabolites are attracting more and more attention all over the world. This review discusses the recent progress in research on the anti-HSV activities of these natural compounds obtained from marine organisms, relating to their structural features and the structure-activity relationships. In addition, the recent findings on the different anti-HSV mechanisms and molecular targets of marine compounds and their potential for therapeutic application will also be summarized in detail.
... Recent studies have shown that a sea urchin pigment known as spinochromes has cytotoxic activity against the human prostate (Dyshlovoy et al., 2020) and neuro-2a neuroblastoma cancer cells in mice (Polonik et al., 2020). It has been found to have several biological effects, including antiviral activity against HSV-1 infection at various stages of Vero cells (Mishchenko et al., 2020). Sea urchin quinone pigments, especially equinochrome and spinochrome, are known to have potent antioxidant, antibacterial, antifungal, and anticancer properties (Ageenko et al., 2014). ...
Introduction: The Persian Gulf is home to a diverse range of marine life, including various species of fish, crustaceans, mollusks, and echinoderms. This study investigates the potential therapeutic properties of venoms from echinoderms in the Persian Gulf, specifically their ability to inhibit cholinesterases (Acetylcholinesterase and butyrylcholinesterase) and act as antioxidants.
Methods: Four venoms from two echinoderm species, including the spine, gonad, and coelomic fluids of sea urchins, as well as brittle star venoms, were analyzed using various methods, including LD50 determination, protein analysis, antioxidant assays, GC-MS for secondary metabolite identification, and molecular docking simulations.
Results and discussion: The study’s results revealed the LD50 of the samples as follows: 2.231 ± 0.09, 1.03 ± 0.05, 1.12 ± 0.13, and 6.04 ± 0.13 mg/mL, respectively. Additionally, the protein levels were 44.037 ± 0.002, 74.223 ± 0.025, 469.97 ± 0.02, and 104.407 ± 0.025 μg/mL, respectively. SDS-PAGE and total protein studies indicated that at least part of the venom was proteinaceous. Furthermore, the study found that the brittle star samples exhibited significantly higher antioxidant activity compared to other samples, including the standard ascorbic acid, at all tested concentrations. GC-MS analysis identified 12, 23, 21, and 25 compounds in the samples, respectively. These compounds had distinct chemical and bioactive structures, including alkaloids, terpenes, and steroids.
Conclusion: These venoms displayed strong cholinesterase inhibitory and antioxidant activities, likely attributed to their protein content and the presence of alkaloids, terpenes, and steroids. Notably, the alkaloid compound C 7 was identified as a promising candidate for further research in Alzheimer’s disease therapy. In conclusion, echinoderms in the Persian Gulf may hold significant potential for discovering novel therapeutic agents.
... (Figure 10). Echinamines A and B are antioxidants isolated from the sea urchin Scaphechinus mirabilis [79], which suppress herpes simplex virus type 1 infection in the Vero monkey kidney cell line [80]. COMPARE analysisderived 1,4-benzoxazepines 13a-d are unreported, giving ( Figure 3) very strong correlations to pleurotin anticancer activity (PCC = 0.8-0.9), ...
This review uses the National Cancer Institute (NCI) COMPARE program to establish an extensive list of heterocyclic iminoquinones and quinones with similarities in differential growth inhibition patterns across the 60-cell line panel of the NCI Developmental Therapeutics Program (DTP). Many natural products and synthetic analogues are revealed as potential
NAD(P)H:quinone oxidoreductase 1 (NQO1) substrates, through correlations to dipyridoimidazo[5,4-f]benzimidazoleiminoquinone (DPIQ), and as potential thioredoxin reductase (TrxR) inhibitors,
through correlations to benzo[1,2,4]triazin-7-ones and pleurotin. The strong correlation to NQO1 infers the enzyme has a major influence on the amount of the active compound with benzo[e]perimidines, phenoxazinones, benz[f]pyrido[1,2-a]indole-6,11-quinones, seriniquinones, kalasinamide, indolequinones, and furano[2,3-b]naphthoquinones, hypothesised as prodrugs. Compounds with very strong correlations to known TrxR inhibitors had inverse correlations to the expression of both reductase enzymes, NQO1 and TrxR, including naphtho[2,3-b][1,4]oxazepane-6,11-diones, benzo[a]carbazole-1,4-diones, pyranonaphthoquinones (including kalafungin, nanaomycin A, and analogues of griseusin
A), and discorhabdin C. Quinoline-5,8-dione scaffolds based on streptonigrin and lavendamycin can correlate to either reductase. Inhibitors of TrxR are not necessarily (imino)quinones, e.g., parthenolides, while oxidising moieties are essential for correlations to NQO1, as with the mitosenes. Herein, an overview of synthetic methods and biological activity of each family of heterocyclic imino(quinone) is provided.
... Naphtho [2,3-b] [1,4]oxazepine-6,11-dione COMPARE gave almost perfect PCC of ~0.90 for the anti-cancer activity of benzo [1,2,4]triazinone 5a to 1,4-benzoxazepine derivatives of 5,8-dihydroxy-1,4-naphthoquinones 13a-d (related to Echinamines A and B) ( Figure 10). Echinamines A and B are antioxidants isolated from the sea urchin Scaphechinus mirabilis [79], which suppress herpes simplex virus type 1 infection in the Vero monkey kidney cell line [80]. COMPARE analysis derived 1,4-benzoxazepines 13a-d are unreported, giving analogous to 5a-d ( Figure 3) very strong correlations to pleurotin anticancer activity (PCC = 0.8-0.9). ...
This review uses the National Cancer Institute (NCI) COMPARE program to establish an extensive list of heterocyclic iminoquinones and quinones with similarities in differential growth inhibition across the 60-cell line panel of the NCI Developmental Therapeutic Program (DTP). Many natural products and synthetic analogues are revealed, as potential NAD(P)H:quinone oxidoreductase 1 (NQO1) substrates through correlations to dipyridoimidazo[5,4-f]benzimidazoleiminoquinone (DPIQ), and as potential thioredoxin reductase (TrxR) inhibitors, through correlations to benzo[1,2,4]triazin-7-ones and pleurotin. The strong correlation to NQO1 infers the enzyme has a major influence on the amount of active compound with benzo[e]perimidines, phenoxazinones, benz[f]pyrido[1,2-a]indole-6,11-quinones, seriniquinones, kalasinamide, indolequinones, and furano[2,3-b]naphthoquinones, hypothesized as prodrugs. Compounds with very strong correlations to known TrxR inhibitors had inverse correlations to the expression of both reductase enzymes, NQO1 and TrxR, including naphtho[2,3-b][1,4]oxazepane-6,11-diones, benzo[a]carbazole-1,4-diones, pyranonaphthoquinones (including kalafungin, nanomycin A, and analogues of griseusin A), and discorhabdin C. Quinoline-5,8-dione scaffolds based on streptonigrin and lavendamycin can correlate to either reductase. Inhibitors of TrxR are not necessarily (imino)quinones, e.g., parthenolides, while oxidizing moieties are essential for correlations to NQO1, as with the mitosenes. Herein, an overview of synthetic methods and biological activity of each family of heterocyclic imino(quinone) is provided.
... Sea urchin is one of the many marine biota created for medications [7][8][9][10][11][12] . More than 5000 chemical compounds with high pharmacological potential have been isolated and described from marine organisms 8 . ...
... The antiviral activity of sea urchin is probably due to the virus-inhibiting activity of the compounds and because of their natural potentially antioxidant properties 7 such as spinochrome, echinochrome, and naphtoquinone pigments 9,10 . According to studies (Mishchenko et al., 2020), the Spinochrome amine present in sea urchins has the ability to suppress the attachment and penetration herpes simplex virus type 1 into the cell 11 . According to Krylova et al., (2019) and Fedoreyevet al., (2018) Oral administration of the antioxidant composition of echinochrome A, ascorbic acid and á-tocopherol (5:5:1) protected 90% of the infected mice against death and reduced vaginal viral loads 7 and affect virus particle of tick-borne encephalitis virus (TBEV) and herpes simplex virus type 1 (HSV-1) 12 . ...
SARS-CoV-2 is a kind of coronavirus that produces Covid-19 illness, which is still a public health concern in Indonesia. Meanwhile, an effective drug has not yet been found and although vaccination has been carried out, in several regions and neighboring countries there is still an increase in Covid-19 cases. This study aimed to obtain bioactive compounds from sea urchins (Echinometra mathaei) that have greater antiviral potential and lower toxicity than remdesivir. This research was started by predicting druglikeness with SwissADME, followed ADMET predicition with pkCSM online, and docking of molecule using the Molegro Virtual Docker (MVD) 5.5 software against the main protease (Mpro) target (PDB ID: 6W63). The results showed that six compounds from sea urchins (Echinometra mathaei) had antiviral activity, where the bioactive compound from sea urchins (Echinometra mathaei) with the highest affinity was shown by Spinochrome C a smaller rerank score compared with Remdesivir and native ligand (X77). So that Spinochrome C compounds are candidates as SARS-CoV-2 inhibitors potential developed drug.
... Some studies also reported multiple mechanisms of anti-HSV-1 action of stilbenes isolated from various plants, including inhibition of virus adsorption and entry, reduction in gene expression, inhibiting the late viral protein synthesis, and stimulation of ROS production [29,[36][37][38]. However, the most probable mechanism of antiherpetic activity of Maksar ® and its components 1 and 4 (Table 4, Figure 2) may be due to their ability to reduce ROS level, induced by HSV-1 in cells [39]. Hence, further study of the mechanisms of HSV-1 inhibition by stilbenes from M. amurensis is necessary. ...
... The cytotoxicity evaluation of the studied compounds was performed using the MTT assay, as described previously [39]. In brief, confluent Vero cells in 96-well microplates (1 × 10 4 cells/well) were incubated with tested compounds at various concentrations (1-500 µg/mL) at 37 • C for 48 h (5% CO 2 ). ...
In this study, we isolated a new isoflavanostilbene maackiapicevestitol (1) as a mixture of two stable conformers 1a and 1b as well as five previously known dimeric and monomeric stilbens: piceatannol (2), maackin (3), scirpusin A (4), maackiasine (5), and maackolin (6) from M. amurensis heartwood, using column chromatography on polyamide, silicagel, and C-18. The structures of these compounds were elucidated by NMR, HR-MS, and CD techniques. Maksar® obtained from M. amurensis heartwood and polyphenolics 1–6 possessed moderate anti-HSV-1 activity in cytopathic effect (CPE) inhibition and RT-PCR assays. A model of PQ-induced neurotoxicity was used to study the neuroprotective potential of polyphenolic compounds from M. amurensis. Maksar® showed the highest neuroprotective activity and increased cell viability by 18% at a concentration of 10 μg/mL. Maackolin (6) also effectively increased the viability of PQ-treated Neuro-2a cells and the value of mitochondrial membrane potential at concentrations up to 10 μΜ. Maksar® and compounds 1–6 possessed higher FRAP and DPPH-scavenging effects than quercetin. However, only compounds 1 and 4 at concentrations of 10 μM as well as Maksar® (10 μg/mL) statistically significantly reduced the level of intracellular ROS in PQ-treated Neuro-2a cells.
... As previously shown, Ech exerts significant anti-HSV-1 activity, mainly due to its direct virucidal properties [19,20]. Ech also showed a moderate inhibitory effect at the early stage of a viral infection, when the test compound simultaneously affects both HSV-1 and Vero cells, but it did not suppress HSV-1 replication when it treated infected cells (virus-inhibiting effect). ...
Herpes simplex virus (HSV) infections, the incidence of which is still widespread throughout the world, are actualizing the search and development of new, more effective antiherpetic drugs. The development of multifunctional drug delivery systems, including liposome-based ones, has become a relevant and attractive concept in nanotechnology. The ability of complexes of κ- and Σ-carrageenans (CRGs)—sulfated polysaccharides of red algae, with echinochrome A (Ech), as well as the liposomal form of the Σ-CRG/Ech complex—to inhibit different stages of HSV-1 infection in Vero cells was studied. By quantum chemical calculations, it was shown that CRG forms stable complexes with Ech. We have shown that complexes of κ-CRG/Ech and Σ-CRG/Ech exhibit highest virucidal activity with a selectivity index (SI) of 270 and 350, respectively, and inhibition of virus-cell interaction (SI of 83 and 32, respectively). The liposomal form of the Σ-CRG/Ech complex after virus adsorption and penetration to cells effectively reduced the HSV-1 plaque formation. The virus-inhibiting activity of the liposomal form of the Σ-CRG/Ech complex was three times higher than that of the Σ-CRG/Ech complex itself. Obtaining CRGs/Ech complexes and their liposomal forms can become the basis of a successful strategy for the development of promising antiherpetic drugs.
... Sea urchins are widely used in traditional Chinese medicine (Hou et al., 2018). Naphthoquinones of the spinochrome class have high biological activity and are promising for the preparation of therapeutic and cosmetic drugs (Brasseur et al., 2017;Fedoreyev et al., 2018;Mishchenko et al., 2020;Vasileva et al., 2021;Vo et al., 2020). ...
There is an opinion that the biological activity of chemical compounds derived from natural raw materials and that of artificially synthesized compounds (analogues of natural substances) may differ. This assumption, however, is still poorly supported by serious scientific research. In our work, we compared a chloroform solution of synthetic juglone (5-hydroxy-1,4-naphthoquinone) and a chloroform extract from a mesocarp of Manchurian walnut (Juglans mandshurica Maxim. (1856)) using the nuclear magnetic resonance (NMR) method to identify possible differences. Research has shown that synthetic and natural juglone are completely identical. This is confirmed by the coincidence of the NMR signals in the spectra of both substances. Differences were found in the content of impurities, although their content is very insignificant and does not exceed 0.1%. With a 15-fold increase in the spectrum of synthetic juglone in the range of 1.5-3.75 ppm, it was seen that the mixture under study contains water in two forms: free and bound (in salts). The presence of these signals allows us to conclude that salts are one of the main impurities in the synthetic juglone sample. The results showed that different forms of 5-hydroxy-1,4-naphthoquinone are present in the synthesized juglone and Manchurian walnut pericarp extract.
