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Special Issue "Marine Bioactive Peptides: Structure, Function, and Therapeutic Potential"

A special issue of Marine Drugs (ISSN 1660-3397).

Deadline for manuscript submissions: closed (30 April 2019)

Special Issue Editor

Guest Editor
Prof. Dr. Tatiana V. Ovchinnikova

Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
Website | E-Mail
Phone: +7-495-336-44-44

Special Issue Information

Dear Colleagues,

This Special Issue, “Marine Bioactive Peptides: Structure, Function, and Therapeutic Potential" will include up-to-date information regarding bioactive peptides isolated from marine organisms. Marine peptides have been found in various phyla, and their numbers have grown in recent years. These peptides are diverse in structure and possess broad-spectrum activities that have great potential for medical applications. Various marine peptides are evolutionary ancient molecular factors of innate immunity that play a key role in host defense. A plethora of biological activities, including antibacterial, antifungal, antiviral, anticancer, anticoagulant, endotoxin-binding, immune-modulating, etc., make marine peptides an attractive molecular basis for drug design. This Special Issue will present new results in the isolation, structural elucidation, functional characterization, and therapeutic potential evaluation of peptides found in marine organisms. Chemical synthesis and biotechnological production of marine peptides and their mimetics will also be a focus of this Special Issue.

Prof. Dr. Tatiana V. Ovchinnikova
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Marine Drugs is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • marine peptides
  • structure
  • function
  • chemical synthesis
  • biotechnological production
  • therapeutic potential
  • antibacterial
  • antifungal
  • antiviral
  • anticancer
  • anticoagulant
  • endotoxin-binding
  • host defense
  • innate immunity
  • peptide drugs
  • toxins

Published Papers (18 papers)

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Research

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Open AccessArticle
Antihypertensive Effect in Vivo of QAGLSPVR and Its Transepithelial Transport Through the Caco-2 Cell Monolayer
Mar. Drugs 2019, 17(5), 288; https://doi.org/10.3390/md17050288
Received: 23 March 2019 / Revised: 17 April 2019 / Accepted: 25 April 2019 / Published: 13 May 2019
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Abstract
The peptide QAGLSPVR, which features high angiotensin-I-converting enzyme (ACE) inhibitory activity, was identified in our previous study. In this study, the in vivo antihypertensive effect of QAGLSPVR was evaluated. Results showed that QAGLSPVR exerts a clear antihypertensive effect on spontaneously hypertensive rats (SHRs), [...] Read more.
The peptide QAGLSPVR, which features high angiotensin-I-converting enzyme (ACE) inhibitory activity, was identified in our previous study. In this study, the in vivo antihypertensive effect of QAGLSPVR was evaluated. Results showed that QAGLSPVR exerts a clear antihypertensive effect on spontaneously hypertensive rats (SHRs), and the systolic and diastolic blood pressures of the rats remarkably decreased by 41.86 and 40.40 mm Hg, respectively, 3 h after peptide administration. The serum ACE activities of SHRs were determined at different times, and QAGLSPVR was found to decrease ACE activities in serum; specifically, minimal ACE activity was found 3 h after administration. QAGLSPVR could be completely absorbed by the Caco-2 cell monolayer, and its transport percentage was 3.5% after 2 h. The transport route results of QAGLSPVR showed that Gly-Sar and wortmannin exert minimal effects on the transport percentage of the peptide (p> 0.05), thus indicating that QAGLSPVR transport through the Caco-2 cell monolayer is not mediated by peptide transporter 1 or transcytosis. By contrast, cytochalasin D significantly increased QAGLSPVR transport (p< 0.05); thus, QAGLSPVR may be transported through the Caco-2 cell monolayer via the paracellular pathway. Full article
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Open AccessFeature PaperArticle
Protective Effect of Pyropia yezoensis Peptide on Dexamethasone-Induced Myotube Atrophy in C2C12 Myotubes
Mar. Drugs 2019, 17(5), 284; https://doi.org/10.3390/md17050284
Received: 11 April 2019 / Revised: 9 May 2019 / Accepted: 10 May 2019 / Published: 11 May 2019
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Abstract
Dexamethasone (DEX), a synthetic glucocorticoid, causes skeletal muscle atrophy. This study examined the protective effects of Pyropia yezoensis peptide (PYP15) against DEX-induced myotube atrophy and its association with insulin-like growth factor-I (IGF-I) and the Akt/mammalian target of rapamycin (mTOR)-forkhead box O (FoxO) signaling [...] Read more.
Dexamethasone (DEX), a synthetic glucocorticoid, causes skeletal muscle atrophy. This study examined the protective effects of Pyropia yezoensis peptide (PYP15) against DEX-induced myotube atrophy and its association with insulin-like growth factor-I (IGF-I) and the Akt/mammalian target of rapamycin (mTOR)-forkhead box O (FoxO) signaling pathway. To elucidate the molecular mechanisms underlying the effects of PYP15 on DEX-induced myotube atrophy, C2C12 myotubes were treated for 24 h with 100 μM DEX in the presence or absence of 500 ng/mL PYP15. Cell viability assays revealed no PYP15 toxicity in C2C12 myotubes. PYP15 activated the insulin-like growth factor-I receptor (IGF-IR) and Akt-mTORC1 signaling pathway in DEX-induced myotube atrophy. In addition, PYP15 markedly downregulated the nuclear translocation of transcription factors FoxO1 and FoxO3a, and inhibited 20S proteasome activity. Furthermore, PYP15 inhibited the autophagy-lysosomal pathway in DEX-stimulated myotube atrophy. Our findings suggest that PYP15 treatment protected against myotube atrophy by regulating IGF-I and the Akt-mTORC1-FoxO signaling pathway in skeletal muscle. Therefore, PYP15 treatment appears to exert protective effects against skeletal muscle atrophy. Full article
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Open AccessArticle
A Novel Peptide from Abalone (Haliotis discus hannai) to Suppress Metastasis and Vasculogenic Mimicry of Tumor Cells and Enhance Anti-Tumor Effect In Vitro
Mar. Drugs 2019, 17(4), 244; https://doi.org/10.3390/md17040244
Received: 18 March 2019 / Revised: 6 April 2019 / Accepted: 19 April 2019 / Published: 24 April 2019
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Abstract
Vasculogenic mimicry (VM) formed by tumor cells plays a vital role in the progress of tumor, because it provides nutrition for tumor cells and takes away the metabolites. Therefore, the inhibition of VM is crucial to the clinical treatment of tumors. In this [...] Read more.
Vasculogenic mimicry (VM) formed by tumor cells plays a vital role in the progress of tumor, because it provides nutrition for tumor cells and takes away the metabolites. Therefore, the inhibition of VM is crucial to the clinical treatment of tumors. In this study, we investigated the anti-tumor effect of a novel peptide, KVEPQDPSEW (AATP), isolated from abalone (Haliotis discus hannai) on HT1080 cells by migration, invasion analysis and the mode of action. The results showed that AATP effectively inhibited MMPs by blocking MAPKs and NF-κB pathways, leading to the downregulation of metastasis of tumor cells. Moreover, AATP significantly inhibited VM and pro-angiogenic factors, including VEGF and MMPs by suppression of AKT/mTOR signaling. In addition, molecular docking was used to study the interaction of AATP and HIF-1α, and the results showed that AATP was combined with an active site of HIF-1α by a hydrogen bond. The effect of AATP on anti-metastatic and anti-vascular in HT1080 cells revealed that AATP may be a potential lead compound for treatment of tumors in the future. Full article
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Open AccessArticle
High-Throughput Identification and Analysis of Novel Conotoxins from Three Vermivorous Cone Snails by Transcriptome Sequencing
Mar. Drugs 2019, 17(3), 193; https://doi.org/10.3390/md17030193
Received: 21 February 2019 / Revised: 19 March 2019 / Accepted: 25 March 2019 / Published: 26 March 2019
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Abstract
The venom of each Conus species consists of a diverse array of neurophysiologically active peptides, which are mostly unique to the examined species. In this study, we performed high-throughput transcriptome sequencing to extract and analyze putative conotoxin transcripts from the venom ducts of [...] Read more.
The venom of each Conus species consists of a diverse array of neurophysiologically active peptides, which are mostly unique to the examined species. In this study, we performed high-throughput transcriptome sequencing to extract and analyze putative conotoxin transcripts from the venom ducts of 3 vermivorous cone snails (C. caracteristicus, C. generalis, and C. quercinus), which are resident in offshore waters of the South China Sea. In total, 118, 61, and 48 putative conotoxins (across 22 superfamilies) were identified from the 3 Conus species, respectively; most of them are novel, and some possess new cysteine patterns. Interestingly, a series of 45 unassigned conotoxins presented with a new framework of C-C-C-C-C-C, and their mature regions were sufficiently distinct from any other known conotoxins, most likely representing a new superfamily. O- and M-superfamily conotoxins were the most abundant in transcript number and transcription level, suggesting their critical roles in the venom functions of these vermivorous cone snails. In addition, we identified numerous functional proteins with potential involvement in the biosynthesis, modification, and delivery process of conotoxins, which may shed light on the fundamental mechanisms for the generation of these important conotoxins within the venom duct of cone snails. Full article
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Open AccessArticle
Anti-Proliferation Activity of a Decapeptide from Perinereies aibuhitensis toward Human Lung Cancer H1299 Cells
Mar. Drugs 2019, 17(2), 122; https://doi.org/10.3390/md17020122
Received: 1 February 2019 / Revised: 11 February 2019 / Accepted: 15 February 2019 / Published: 18 February 2019
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Abstract
Perinereis aibuhitensis peptide (PAP) is a decapeptide (Ile-Glu-Pro-Gly-Thr-Val-Gly-Met-Met-Phe, IEPGTVGMMF) with anticancer activity that was purified from an enzymatic hydrolysate of Perinereis aibuhitensis. In the present study, the anticancer effect of PAP on H1299 cell proliferation was investigated. Our results showed that PAP [...] Read more.
Perinereis aibuhitensis peptide (PAP) is a decapeptide (Ile-Glu-Pro-Gly-Thr-Val-Gly-Met-Met-Phe, IEPGTVGMMF) with anticancer activity that was purified from an enzymatic hydrolysate of Perinereis aibuhitensis. In the present study, the anticancer effect of PAP on H1299 cell proliferation was investigated. Our results showed that PAP promoted apoptosis and inhibited the proliferation of H1299 cells in a time- and dose-dependent manner. When the PAP concentration reached 0.92 mM, more than 95% of treated cells died after 72 h of treatment. Changes in cell morphology were further analyzed using an inverted microscope and AO/EB staining and flow cytometry was adopted for detecting apoptosis and cell cycle phase. The results showed that the early and late apoptosis rates of H1299 cells increased significantly after treatment with PAP and the total apoptosis rate was significantly higher than that of the control group. Moreover, after treatment with PAP, the number of cells in the S phase of cells was significantly reduced and the ability for the cells to proliferate was also reduced. H1299 cells were arrested in the G2/M phase and cell cycle progression was inhibited. Furthermore, the results of western blotting showed that nm23-H1 and vascular endothelial growth factor (VEGF) protein levels decreased in a dose-dependent manner, while the pro-apoptotic protein and anti-apoptotic protein ratios and the level of apoptosis-related caspase protein increased in a dose-dependent manner. In conclusion, our results indicated that PAP, as a natural marine bioactive substance, inhibited proliferation and induced apoptosis of human lung cancer H1299 cells. PAP is likely to be exploited as the functional food or adjuvant that may be used for prevention or treatment of human non-small cell lung cancer in the future. Full article
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Open AccessArticle
Novel Antibacterial Peptides Isolated from the Maillard Reaction Products of Half-Fin Anchovy (Setipinna taty) Hydrolysates/Glucose and Their Mode of Action in Escherichia Coli
Mar. Drugs 2019, 17(1), 47; https://doi.org/10.3390/md17010047
Received: 19 November 2018 / Revised: 7 January 2019 / Accepted: 8 January 2019 / Published: 10 January 2019
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Abstract
The Maillard reaction products (MRPs) of half-fin anchovy hydrolysates and glucose, named as HAHp(9.0)-G MRPs, were fractionated by size exclusion chromatography into three major fractions (F1–F3). F2, which demonstrated the strongest antibacterial activity against Escherichia coli (E. coli) and showed self-production [...] Read more.
The Maillard reaction products (MRPs) of half-fin anchovy hydrolysates and glucose, named as HAHp(9.0)-G MRPs, were fractionated by size exclusion chromatography into three major fractions (F1–F3). F2, which demonstrated the strongest antibacterial activity against Escherichia coli (E. coli) and showed self-production of hydrogen peroxide (H2O2), was extracted by solid phase extraction. The hydrophobic extract of F2 was further isolated by reverse phase-high performance liquid chromatography into sub-fractions HE-F2-1 and HE-F2-2. Nine peptides were identified from HE-F2-1, and two peptides from HE-F2-2 using liquid chromatography-electrospray ionization/multi-stage mass spectrometry. Three peptides, FEDQLR (HGM-Hp1), ALERTF (HGM-Hp2), and RHPEYAVSVLLR (HGM-Hp3), with net charges of −1, 0, and +1, respectively, were synthesized. The minimal inhibitory concentration of these synthetic peptides was 2 mg/mL against E. coli. Once incubated with logarithmic growth phase of E. coli, HGM-Hp1 and HGM-Hp2 induced significant increases of both extracellular and intracellular H2O2 formation. However, HGM-Hp3 only dramatically enhanced intracellular H2O2 production in E. coli. The increased potassium ions in E. coli suspension after addition of HGM-Hp1 or HGM-Hp2 indicated the destruction of cell integrity via irreversible membrane damage. It is the first report of hydrolysates MRPs-derived peptides that might perform the antibacterial activity via inducing intracellular H2O2 production. Full article
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Open AccessArticle
Preparation, Identification, and Activity Evaluation of Eight Antioxidant Peptides from Protein Hydrolysate of Hairtail (Trichiurus japonicas) Muscle
Mar. Drugs 2019, 17(1), 23; https://doi.org/10.3390/md17010023
Received: 12 November 2018 / Revised: 25 December 2018 / Accepted: 26 December 2018 / Published: 2 January 2019
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Abstract
In this report, protein of hairtail (Trichiurus japonicas) muscle was separately hydrolyzed using five kinds of proteases (alcalase, trypsin, neutrase, pepsin, and papain), and the papain- and alcalase-hydrolysates showed higher 2,2-diphenyl-1-picrylhydrazyl radicals (DPPH•) and hydroxyl radical (HO•) scavenging activity than other [...] Read more.
In this report, protein of hairtail (Trichiurus japonicas) muscle was separately hydrolyzed using five kinds of proteases (alcalase, trypsin, neutrase, pepsin, and papain), and the papain- and alcalase-hydrolysates showed higher 2,2-diphenyl-1-picrylhydrazyl radicals (DPPH•) and hydroxyl radical (HO•) scavenging activity than other three protease hydrolysates. Therefore, the protein hydrolysate of hairtail muscle (HTP) was prepared using binary-enzymes hydrolysis process (papain + alcalase). Subsequently, eight antioxidant peptides were purified from HTP using membrane ultrafiltration and chromatography technology, and their amino acid sequences were identified as Gln-Asn-Asp-Glu-Arg (TJP1), Lys-Ser (TJP2), Lys-Ala (TJP3), Ala-Lys-Gly (TJP4), Thr-Lys-Ala (TJP5), Val-Lys (TJP6), Met-Lys (TJP7), and Ile-Tyr-Gly (TJP8) with molecular weights of 660.3, 233.0, 217.1, 274.1, 318.0, 245.1, 277.0, and 351.0 Da, respectively. TJP3, TJP4, and TJP8 exhibited strong scavenging activities on DPPH• (EC50 0.902, 0.626, and 0.663 mg/mL, respectively), HO• (EC50 1.740, 2.378, and 2.498 mg/mL, respectively), superoxide anion radical (EC50 2.082, 2.538, and 1.355 mg/mL, respectively), and 2,2′-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical (EC50 1.652, 0.831, and 0.586 mg/mL, respectively). Moreover, TJP3, TJP4, and TJP8 showed higher reducing power and inhibiting ability on lipid peroxidation in a linoleic acid model system. These results suggested that eight isolated peptides (TJP1 to TJP8), especially TJP3, TJP4, and TJP8 might serve as potential antioxidants applied in the pharmaceutical and health food industries. Full article
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Open AccessArticle
Analgesic Activity of Acid-Sensing Ion Channel 3 (ASIС3) Inhibitors: Sea Anemones Peptides Ugr9-1 and APETx2 versus Low Molecular Weight Compounds
Mar. Drugs 2018, 16(12), 500; https://doi.org/10.3390/md16120500
Received: 28 September 2018 / Revised: 5 December 2018 / Accepted: 10 December 2018 / Published: 12 December 2018
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Abstract
Acid-sensing ion channel 3 (ASIC3) makes an important contribution to the development and maintenance of inflammatory and acid-induced pain. We compared different ASIC3 inhibitors (peptides from sea anemones (APETx2 and Ugr9-1) and nonpeptide molecules (sevanol and diclofenac)) in anti-inflammatory action and analgesic effects. [...] Read more.
Acid-sensing ion channel 3 (ASIC3) makes an important contribution to the development and maintenance of inflammatory and acid-induced pain. We compared different ASIC3 inhibitors (peptides from sea anemones (APETx2 and Ugr9-1) and nonpeptide molecules (sevanol and diclofenac)) in anti-inflammatory action and analgesic effects. All tested compounds had distinct effects on pH-induced ASIC3 current. APETx2 inhibited only transient current, whereas Ugr9-1 and sevanol decreased transient and sustained components of the current. The effect on mice was evaluated after administering an intramuscular injection in the acetic acid writhing pain model and the complete Freund’s adjuvant-induced thermal hyperalgesia/inflammation test. The bell-shaped dependence of the analgesic effect was observed for APETx2 in the acetic acid-induced writhing test, as well as for sevanol and peptide Ugr9-1 in the thermal hyperalgesia test. This dependence could be evidence of the nonspecific action of compounds in high doses. Compounds reducing both components of ASIC3 current produced more significant pain relief than APETx2, which is an effective inhibitor of a transient current only. Therefore, the comparison of the efficacy of ASIC3 inhibitors revealed the importance of ASIC3-sustained currents’ inhibition for promotion of acidosis-related pain relief. Full article
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Open AccessArticle
Modulation of Human Complement System by Antimicrobial Peptide Arenicin-1 from Arenicola marina
Mar. Drugs 2018, 16(12), 480; https://doi.org/10.3390/md16120480
Received: 17 October 2018 / Revised: 13 November 2018 / Accepted: 27 November 2018 / Published: 1 December 2018
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Abstract
Antimicrobial peptides from marine invertebrates are known not only to act like cytotoxic agents, but they also can display some additional activities in mammalian organisms. In particular, these peptides can modulate the complement system as was described for tachyplesin, a peptide from the [...] Read more.
Antimicrobial peptides from marine invertebrates are known not only to act like cytotoxic agents, but they also can display some additional activities in mammalian organisms. In particular, these peptides can modulate the complement system as was described for tachyplesin, a peptide from the horseshoe crab. In this work, we investigated the influence on complement activation of the antimicrobial peptide arenicin-1 from the marine polychaete Arenicola marina. To study effects of arenicin on complement activation in human blood serum, we used hemolytic assays of two types, with antibody sensitized sheep erythrocytes and rabbit erythrocytes. Complement activation was also assessed, by the level of C3a production that was measured by ELISA. We found that the effect of arenicin depends on its concentration. At relatively low concentrations the peptide stimulates complement activation and lysis of target erythrocytes, whereas at higher concentrations arenicin acts as a complement inhibitor. A hypothetical mechanism of peptide action is proposed, suggesting its interaction with two complement proteins, C1q and C3. The results lead to the possibility of the development of new approaches for therapy of diseases connected with complement dysregulation, using peptide regulators derived from natural antimicrobial peptides of invertebrates. Full article
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Open AccessArticle
Two Novel Multi-Functional Peptides from Meat and Visceral Mass of Marine Snail Neptunea arthritica cumingii and Their Activities In Vitro and In Vivo
Mar. Drugs 2018, 16(12), 473; https://doi.org/10.3390/md16120473
Received: 31 October 2018 / Revised: 20 November 2018 / Accepted: 22 November 2018 / Published: 27 November 2018
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Abstract
Neptunea arthritica cumingii (Nac) is a marine snail with high nutritional and commercial value; however, little is known about its active peptides. In this study, two multi-functional peptides, YSQLENEFDR (Tyr-Ser-Gln-Leu-Glu-Asn-Glu-Phe-Asp-Arg) and YIAEDAER (Tyr-Ile-Ala-Glu-Asp-Ala-Glu-Arg), were isolated and purified from meat and visceral [...] Read more.
Neptunea arthritica cumingii (Nac) is a marine snail with high nutritional and commercial value; however, little is known about its active peptides. In this study, two multi-functional peptides, YSQLENEFDR (Tyr-Ser-Gln-Leu-Glu-Asn-Glu-Phe-Asp-Arg) and YIAEDAER (Tyr-Ile-Ala-Glu-Asp-Ala-Glu-Arg), were isolated and purified from meat and visceral mass extracts of Nac using a multi-bioassay-guided method and were characterized by using liquid chromatography-tandem mass spectrometry. Both peptides showed high antioxidant, angiotensin-converting enzyme (ACE)-inhibitory, and anti-diabetic activities, with half-maximal effective concentrations values less than 1 mM. Antioxidant and ACE-inhibitory activities were significantly higher for YSQLENEFDR than for YIAEDAER. In a zebrafish model, the two peptides exhibited strong scavenging ability for reactive oxygen species and effectively protected skin cells against oxidative damage without toxicity. Molecular docking simulation further predicted the interactions of the two peptides and ACE. Stability analysis study indicated that the two synthetic peptides maintained their activities under thermal stress and simulated gastrointestinal digestion conditions. The low molecular weight, high proportion of hydrophobic and negatively-charged amino acids, and specific C-terminal and N-terminal amino acids may contribute to the observed bio-activities of these two peptides with potential application for the prevention of chronic noncommunicable diseases. Full article
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Open AccessArticle
Cytotoxic Potential of the Novel Horseshoe Crab Peptide Polyphemusin III
Mar. Drugs 2018, 16(12), 466; https://doi.org/10.3390/md16120466
Received: 3 November 2018 / Revised: 19 November 2018 / Accepted: 20 November 2018 / Published: 26 November 2018
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Abstract
Biological activity of the new antimicrobial peptide polyphemusin III from the horseshoe crab Limulus polyphemus was examined against bacterial strains and human cancer, transformed, and normal cell cultures. Polyphemusin III has the amino acid sequence RRGCFRVCYRGFCFQRCR and is homologous to other β-hairpin peptides [...] Read more.
Biological activity of the new antimicrobial peptide polyphemusin III from the horseshoe crab Limulus polyphemus was examined against bacterial strains and human cancer, transformed, and normal cell cultures. Polyphemusin III has the amino acid sequence RRGCFRVCYRGFCFQRCR and is homologous to other β-hairpin peptides from the horseshoe crab. Antimicrobial activity of the peptide was evaluated and MIC (minimal inhibitory concentration) values were determined. IC50 (half-maximal inhibitory concentration) values measured toward human cells revealed that polyphemusin III showed a potent cytotoxic activity at concentrations of <10 μM. Polyphemusin III caused fast permeabilization of the cytoplasmic membrane of human leukemia cells HL-60, which was measured with trypan blue exclusion assay and lactate dehydrogenase-release assay. Flow cytometry experiments for annexin V-FITC/ propidium iodide double staining revealed that the caspase inhibitor, Z-VAD-FMK, did not abrogate disruption of the plasma membrane by polyphemusin III. Our data suggest that polyphemusin III disrupts the plasma membrane integrity and induces cell death that is apparently not related to apoptosis. In comparison to known polyphemusins and tachyplesins, polyphemusin III demonstrates a similar or lower antimicrobial effect, but significantly higher cytotoxicity against human cancer and transformed cells in vitro. Full article
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Open AccessArticle
Novel Antimicrobial Peptides from the Arctic Polychaeta Nicomache minor Provide New Molecular Insight into Biological Role of the BRICHOS Domain
Mar. Drugs 2018, 16(11), 401; https://doi.org/10.3390/md16110401
Received: 30 September 2018 / Revised: 16 October 2018 / Accepted: 20 October 2018 / Published: 23 October 2018
Cited by 1 | PDF Full-text (4721 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Endogenous antimicrobial peptides (AMPs) are among the earliest molecular factors in the evolution of animal innate immunity. In this study, novel AMPs named nicomicins were identified in the small marine polychaeta Nicomache minor in the Maldanidae family. Full-length mRNA sequences encoded 239-residue prepropeptides [...] Read more.
Endogenous antimicrobial peptides (AMPs) are among the earliest molecular factors in the evolution of animal innate immunity. In this study, novel AMPs named nicomicins were identified in the small marine polychaeta Nicomache minor in the Maldanidae family. Full-length mRNA sequences encoded 239-residue prepropeptides consisting of a putative signal sequence region, the BRICHOS domain within an acidic proregion, and 33-residue mature cationic peptides. Nicomicin-1 was expressed in the bacterial system, and its spatial structure was analyzed by circular dichroism and nuclear magnetic resonance spectroscopy. Nicomicins are unique among polychaeta AMPs scaffolds, combining an amphipathic N-terminal α-helix and C-terminal extended part with a six-residue loop stabilized by a disulfide bridge. This structural arrangement resembles the Rana-box motif observed in the α-helical host-defense peptides isolated from frog skin. Nicomicin-1 exhibited strong in vitro antimicrobial activity against Gram-positive bacteria at submicromolar concentrations. The main mechanism of nicomicin-1 action is based on membrane damage but not on the inhibition of bacterial translation. The peptide possessed cytotoxicity against cancer and normal adherent cells as well as toward human erythrocytes. Full article
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Open AccessArticle
Massive Gene Expansion and Sequence Diversification Is Associated with Diverse Tissue Distribution, Regulation and Antimicrobial Properties of Anti-Lipopolysaccharide Factors in Shrimp
Mar. Drugs 2018, 16(10), 381; https://doi.org/10.3390/md16100381
Received: 15 September 2018 / Revised: 3 October 2018 / Accepted: 9 October 2018 / Published: 11 October 2018
Cited by 2 | PDF Full-text (6270 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Anti-lipopolysaccharide factors (ALFs) are antimicrobial peptides with a central β-hairpin structure able to bind to microbial components. Mining sequence databases for ALFs allowed us to show the remarkable diversity of ALF sequences in shrimp. We found at least seven members of the ALF [...] Read more.
Anti-lipopolysaccharide factors (ALFs) are antimicrobial peptides with a central β-hairpin structure able to bind to microbial components. Mining sequence databases for ALFs allowed us to show the remarkable diversity of ALF sequences in shrimp. We found at least seven members of the ALF family (Groups A to G), including two novel Groups (F and G), all of which are encoded by different loci with conserved gene organization. Phylogenetic analyses revealed that gene expansion and subsequent diversification of the ALF family occurred in crustaceans before shrimp speciation occurred. The transcriptional profile of ALFs was compared in terms of tissue distribution, response to two pathogens and during shrimp development in Litopenaeus vannamei, the most cultivated species. ALFs were found to be constitutively expressed in hemocytes and to respond differently to tissue damage. While synthetic β-hairpins of Groups E and G displayed both antibacterial and antifungal activities, no activity was recorded for Group F β-hairpins. Altogether, our results showed that ALFs form a family of shrimp AMPs that has been the subject of intense diversification. The different genes differ in terms of tissue expression, regulation and function. These data strongly suggest that multiple selection pressures have led to functional diversification of ALFs in shrimp. Full article
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Open AccessArticle
A Novel Natural Influenza A H1N1 Virus Neuraminidase Inhibitory Peptide Derived from Cod Skin Hydrolysates and Its Antiviral Mechanism
Mar. Drugs 2018, 16(10), 377; https://doi.org/10.3390/md16100377
Received: 13 September 2018 / Revised: 27 September 2018 / Accepted: 6 October 2018 / Published: 10 October 2018
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Abstract
In this paper, a novel natural influenza A H1N1 virus neuraminidase (NA) inhibitory peptide derived from cod skin hydrolysates was purified and its antiviral mechanism was explored. From the hydrolysates, novel efficient NA-inhibitory peptides were purified by a sequential approach utilizing an ultrafiltration [...] Read more.
In this paper, a novel natural influenza A H1N1 virus neuraminidase (NA) inhibitory peptide derived from cod skin hydrolysates was purified and its antiviral mechanism was explored. From the hydrolysates, novel efficient NA-inhibitory peptides were purified by a sequential approach utilizing an ultrafiltration membrane (5000 Da), sephadex G-15 gel column and reverse-phase high-performance liquid chromatography (RP-HPLC). The amino acid sequence of the pure peptide was determined by electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI-FTICR-MS) was PGEKGPSGEAGTAGPPGTPGPQGL, with a molecular weight of 2163 Da. The analysis of the Lineweacer–Burk model indicated that the peptide was a competitive NA inhibitor with Ki of 0.29 mM and could directly bind free enzymes. In addition, docking studies suggested that hydrogen binding might be the driving force for the binding affinity of PGEKGPSGEAGTAGPPGTPGPQGL to NA. The cytopathic effect reduction assay showed that the peptide PGEKGPSGEAGTAGPPGTPGPQGL protected Madin–Darby canine kidney (MDCK) cells from viral infection and reduced the viral production in a dose-dependent manner. The EC50 value was 471 ± 12 μg/mL against H1N1. Time-course analysis showed that PGEKGPSGEAGTAGPPGTPGPQGL inhibited influenza virus in the early stage of the infectious cycle. The virus titers assay indicated that the NA-inhibitory peptide PGEKGPSGEAGTAGPPGTPGPQGL could directly affect the virus toxicity and adsorption by host cells, further proving that the peptide had an anti-viral effect with multiple target sites. The activity of NA-inhibitory peptide was almost inactivated during the simulated in vitro gastrointestinal digestion, suggesting that oral administration is not recommended. The peptide PGEKGPSGEAGTAGPPGTPGPQGL acts as a neuraminidase blocker to inhibit influenza A virus in MDCK cells. Thus, the peptide PGEKGPSGEAGTAGPPGTPGPQGL has potential utility in the treatment of the influenza virus infection. Full article
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Open AccessArticle
Inhibition of Prostate Cancer DU-145 Cells Proliferation by Anthopleura anjunae Oligopeptide (YVPGP) via PI3K/AKT/mTOR Signaling Pathway
Mar. Drugs 2018, 16(9), 325; https://doi.org/10.3390/md16090325
Received: 13 August 2018 / Accepted: 6 September 2018 / Published: 11 September 2018
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Abstract
We investigated the antitumor mechanism of Anthopleura anjunae oligopeptide (AAP-H, YVPGP) in prostate cancer DU-145 cells in vitro and in vivo. Results indicated that AAP-H was nontoxic and exhibited antitumor activities. Cell cycle analysis indicated that AAP-H may arrest DU-145 cells in the [...] Read more.
We investigated the antitumor mechanism of Anthopleura anjunae oligopeptide (AAP-H, YVPGP) in prostate cancer DU-145 cells in vitro and in vivo. Results indicated that AAP-H was nontoxic and exhibited antitumor activities. Cell cycle analysis indicated that AAP-H may arrest DU-145 cells in the S phase. The role of the phosphatidylinositol 3-kinase/protein kinase B/mammalian rapamycin target protein (PI3K/AKT/mTOR) signaling pathway in the antitumor mechanism of APP-H was investigated. Results showed that AAP-H treatment led to dose-dependent reduction in the levels of p-AKT (Ser473), p-PI3K (p85), and p-mTOR (Ser2448), whereas t-AKT and t-PI3K levels remained unaltered compared to the untreated DU-145 cells. Inhibition of PI3K/AKT/mTOR signaling pathway in the DU-145 cells by employing inhibitor LY294002 (10 μM) or rapamycin (20 nM) effectively attenuated AAP-H-induced phosphorylation of AKT and mTOR. At the same time, inhibitor addition further elevated AAP-H-induced cleaved-caspase-3 levels. Furthermore, the effect of AAP-H on tumor growth and the role of the PI3K/AKT/mTOR signaling pathway in nude mouse model were also investigated. Immunohistochemical analysis showed that activated AKT, PI3K, and mTOR levels were reduced in DU-145 xenografts. Western blotting showed that AAP-H treatment resulted in dose-dependent reduction in p-AKT (Ser473), p-PI3K (p85), and p-mTOR (Ser2448) levels, whereas t-AKT and t-PI3K levels remained unaltered. Similarly, Bcl-xL levels decreased, whereas that of Bax increased after AAP-H treatment. AAP-H also increased initiator (caspase 8 and 9) and executor caspase (caspase 3 and 7) levels. Therefore, the antitumor mechanism of APP-H on DU-145 cells may involve regulation of the PI3K/AKT/mTOR signaling pathway, which eventually promotes apoptosis via mitochondrial and death receptor pathways. Thus, the hydrophobic oligopeptide (YVPGP) can be developed as an adjuvant for the prevention or treatment of prostate cancer in the future. Full article
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Open AccessArticle
Antihypertensive Effects of Two Novel Angiotensin I-Converting Enzyme (ACE) Inhibitory Peptides from Gracilariopsis lemaneiformis (Rhodophyta) in Spontaneously Hypertensive Rats (SHRs)
Mar. Drugs 2018, 16(9), 299; https://doi.org/10.3390/md16090299
Received: 23 July 2018 / Revised: 10 August 2018 / Accepted: 21 August 2018 / Published: 27 August 2018
Cited by 1 | PDF Full-text (2988 KB) | HTML Full-text | XML Full-text
Abstract
A variety of biologically active products have been isolated from Gracilariopsis lemaneiformis. In the present study, two novel angiotensin-converting enzyme (ACE) inhibitory peptides, FQIN [M(O)] CILR, and TGAPCR, were screened and identified from G. lemaneiformis protein hydrolysates by LC-MS/MS. The IC50 values [...] Read more.
A variety of biologically active products have been isolated from Gracilariopsis lemaneiformis. In the present study, two novel angiotensin-converting enzyme (ACE) inhibitory peptides, FQIN [M(O)] CILR, and TGAPCR, were screened and identified from G. lemaneiformis protein hydrolysates by LC-MS/MS. The IC50 values of FQIN [M(O)] CILR and TGAPCR were 9.64 ± 0.36 μM and 23.94 ± 0.82 μM, respectively. In the stability study, both peptides showed stabilities of pH, temperature, simulated gastrointestinal digestion, and ACE hydrolysis. The Lineweaver–Burk plot showed that the two peptides were noncompetitive inhibitors of ACE. Molecular docking simulated the intermolecular interactions of two peptides and ACE, and the two peptides formed hydrogen bonds with the active pockets of ACE. However, FQIN [M(O)] CILR was more closely linked to the active pockets of ACE, thereby exerting better ACE inhibition. Spontaneously hypertensive rats (SHRs) were studied with an oral dose of 10 mg/kg body weight. Both peptides reduced systolic blood pressure (SBP) and diastolic blood pressure (DBP) in SHRs, of which FQIN [M(O)] CILR was able to reduce the systolic blood pressure by 34 mmHg (SBP) (p < 0.05). Therefore, FQIN [M(O)] CILR was an excellent ACE inhibitory peptide. Full article
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Open AccessArticle
Novel Natural Angiotensin Converting Enzyme (ACE)-Inhibitory Peptides Derived from Sea Cucumber-Modified Hydrolysates by Adding Exogenous Proline and a Study of Their Structure–Activity Relationship
Mar. Drugs 2018, 16(8), 271; https://doi.org/10.3390/md16080271
Received: 13 July 2018 / Revised: 28 July 2018 / Accepted: 2 August 2018 / Published: 4 August 2018
Cited by 1 | PDF Full-text (2798 KB) | HTML Full-text | XML Full-text
Abstract
Natural angiotensin converting enzyme (ACE)-inhibitory peptides, which are derived from marine products, are useful as antihypertensive drugs. Nevertheless, the activities of these natural peptides are relatively low, which limits their applications. The aim of this study was to prepare efficient ACE-inhibitory peptides from [...] Read more.
Natural angiotensin converting enzyme (ACE)-inhibitory peptides, which are derived from marine products, are useful as antihypertensive drugs. Nevertheless, the activities of these natural peptides are relatively low, which limits their applications. The aim of this study was to prepare efficient ACE-inhibitory peptides from sea cucumber-modified hydrolysates by adding exogenous proline according to a facile plastein reaction. When 40% proline (w/w, proline/free amino groups) was added, the modified hydrolysates exhibited higher ACE-inhibitory activity than the original hydrolysates. Among the modified hydrolysates, two novel efficient ACE-inhibitory peptides, which are namely PNVA and PNLG, were purified and identified by a sequential approach combining a sephadex G-15 gel column, reverse-phase high-performance liquid chromatography (RP-HPLC) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS), before we conducted confirmatory studies with synthetic peptides. The ACE-inhibitory activity assay showed that PNVA and PNLG exhibited lower IC50 values of 8.18 ± 0.24 and 13.16 ± 0.39 μM than their corresponding truncated analogs (NVA and NLG), respectively. Molecular docking showed that PNVA and PNLG formed a larger number of hydrogen bonds with ACE than NVA and NLG, while the proline at the N-terminal of peptides can affect the orientation of the binding site of ACE. The method developed in this study may potentially be applied to prepare efficient ACE-inhibitory peptides, which may play a key role in hypertension management. Full article
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Review

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Open AccessReview
Snails In Silico: A Review of Computational Studies on the Conopeptides
Mar. Drugs 2019, 17(3), 145; https://doi.org/10.3390/md17030145
Received: 18 January 2019 / Revised: 21 February 2019 / Accepted: 22 February 2019 / Published: 1 March 2019
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Abstract
Marine cone snails are carnivorous gastropods that use peptide toxins called conopeptides both as a defense mechanism and as a means to immobilize and kill their prey. These peptide toxins exhibit a large chemical diversity that enables exquisite specificity and potency for target [...] Read more.
Marine cone snails are carnivorous gastropods that use peptide toxins called conopeptides both as a defense mechanism and as a means to immobilize and kill their prey. These peptide toxins exhibit a large chemical diversity that enables exquisite specificity and potency for target receptor proteins. This diversity arises in terms of variations both in amino acid sequence and length, and in posttranslational modifications, particularly the formation of multiple disulfide linkages. Most of the functionally characterized conopeptides target ion channels of animal nervous systems, which has led to research on their therapeutic applications. Many facets of the underlying molecular mechanisms responsible for the specificity and virulence of conopeptides, however, remain poorly understood. In this review, we will explore the chemical diversity of conopeptides from a computational perspective. First, we discuss current approaches used for classifying conopeptides. Next, we review different computational strategies that have been applied to understanding and predicting their structure and function, from machine learning techniques for predictive classification to docking studies and molecular dynamics simulations for molecular-level understanding. We then review recent novel computational approaches for rapid high-throughput screening and chemical design of conopeptides for particular applications. We close with an assessment of the state of the field, emphasizing important questions for future lines of inquiry. Full article
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