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Marine Drugs
Special Issues
Marine Drugs Interact with Functional Proteins
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Marine Drugs Interact with Functional Proteins

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

Deadline for manuscript submissions: closed (31 May 2018) | Viewed by 24199

Special Issue Editor

Prof. Masaki Kita

E-Mail Website
Guest Editor
Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan
Interests: Natural products; Biologically and physiologically intriguing phenomena; Spectoscopic analysis; Target identification; Mode of action

Special Issue Information

Dear Colleagues,

It has been shown that a number of marine natural products interact with functional proteins to show potent biological and physiological activities. For example, an anticancer drug, eribulin, derived from the marine macrolide halichondrin B, is a unique inhibitor of microtubule dynamics. Some marine natural products have recently been shown to induce or inhibit protein‒protein interactions. These new mechanistic findings should be useful for the design and development of new pharmacological tools and therapeutic agents.

This Special Issue will highlight the progress in the following topics: Isolation and structures of bioactive marine natural products (such as anti-tumor, anti-bacterial, anti-inflammation, anti-oxidant compounds) that target functional proteins; development and use of chemical probes inspired from bioactive marine natural products; target protein identification and mechanism of action studies; structural and kinetic analysis of protein–ligand interactions; and structure-activity relationship studies and drug discovery study of marine bioactive compounds that interfere in protein dynamics.

Prof. Masaki Kita
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 submissions that pass pre-check are 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 2900 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 natural products
  • Bioactive secondary metabolites
  • Target protein identification
  • Mechanism of action
  • Interference toward protein dynamics including protein–protein interaction
  • Structural and kinetic analysis of protein–ligand interactions
  • Structure-activity relationships
  • Drug discovery

Published Papers (5 papers)

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Research

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9 pages, 1216 KiB  
Communication
(−)-Homosalinosporamide A and Its Mode of Proteasome Inhibition: An X-ray Crystallographic Study
by Michael Groll, Henry Nguyen, Sreekumar Vellalath and Daniel Romo
Mar. Drugs 2018, 16(7), 240; https://doi.org/10.3390/md16070240 - 19 Jul 2018
Cited by 6 | Viewed by 4132
Abstract
Upon acylation of the proteasome by the β-lactone inhibitor salinosporamide A (SalA), tetrahydrofuran formation occurs by intramolecular alkylation of the incipient alkoxide onto the choroethyl sidechain and irreversibly blocks the active site. Our previously described synthetic approach to SalA, utilizing a bioinspired, late-stage, [...] Read more.
Upon acylation of the proteasome by the β-lactone inhibitor salinosporamide A (SalA), tetrahydrofuran formation occurs by intramolecular alkylation of the incipient alkoxide onto the choroethyl sidechain and irreversibly blocks the active site. Our previously described synthetic approach to SalA, utilizing a bioinspired, late-stage, aldol-β-lactonization strategy to construct the bicyclic β-lactone core, enabled synthesis of (–)-homosalinosporamide A (homoSalA). This homolog was targeted to determine whether an intramolecular tetrahydropyran is formed in a similar manner to SalA. Herein, we report the X-ray structure of the yeast 20S proteasome:homoSalA-complex which reveals that tetrahydropyran ring formation does not occur despite comparable potency at the chymotrypsin-like active site in a luminogenic enzyme assay. Thus, the natural product derivative homoSalA blocks the proteasome by a covalent reversible mode of action, opening the door for further fine-tuning of proteasome inhibition. Full article
(This article belongs to the Special Issue Marine Drugs Interact with Functional Proteins)
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14 pages, 3454 KiB  
Communication
A Novel Atypical PKC-Iota Inhibitor, Echinochrome A, Enhances Cardiomyocyte Differentiation from Mouse Embryonic Stem Cells
by Hyoung Kyu Kim, Sung Woo Cho, Hye Jin Heo, Seung Hun Jeong, Min Kim, Kyung Soo Ko, Byoung Doo Rhee, Natalia P. Mishchenko, Elena A. Vasileva, Sergey A. Fedoreyev, Valentin A. Stonik and Jin Han
Mar. Drugs 2018, 16(6), 192; https://doi.org/10.3390/md16060192 - 02 Jun 2018
Cited by 17 | Viewed by 5242
Abstract
Echinochrome A (EchA) is a marine bioproduct extracted from sea urchins having antioxidant, antimicrobial, anti-inflammatory, and chelating effects, and is the active component of the clinical drug histochrome. We investigated the potential use of Ech A for inducing cardiomyocyte differentiation from mouse embryonic [...] Read more.
Echinochrome A (EchA) is a marine bioproduct extracted from sea urchins having antioxidant, antimicrobial, anti-inflammatory, and chelating effects, and is the active component of the clinical drug histochrome. We investigated the potential use of Ech A for inducing cardiomyocyte differentiation from mouse embryonic stem cells (mESCs). We also assessed the effects of Ech A on mitochondrial mass, inner membrane potential (Δψm), reactive oxygen species generation, and levels of Ca2+. To identify the direct target of Ech A, we performed in vitro kinase activity and surface plasmon resonance binding assays. Ech A dose-dependently enhanced cardiomyocyte differentiation with higher beating rates. Ech A (50 μM) increased the mitochondrial mass and membrane potential but did not alter the mitochondrial superoxide and Ca2+ levels. The in vitro kinase activity of the atypical protein kinase C-iota (PKCι) was significantly decreased by 50 μM of Ech A with an IC50 for PKCι activity of 107 μM. Computational protein-ligand docking simulation results suggested the direct binding of Ech A to PKCι, and surface plasmon resonance confirmed the direct binding with a low KD of 6.3 nM. Therefore, Ech A is a potential drug for enhancing cardiomyocyte differentiation from mESCs through direct binding to PKCι and inhibition of its activity. Full article
(This article belongs to the Special Issue Marine Drugs Interact with Functional Proteins)
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15 pages, 24061 KiB  
Article
Structural Characterization and Interaction with RCA120 of a Highly Sulfated Keratan Sulfate from Blue Shark (Prionace glauca) Cartilage
by Qinying Li, Guoyun Li, Xiaoliang Zhao, Xindi Shan, Chao Cai, Jing Zhao, Fuming Zhang, Robert J. Linhardt and Guangli Yu
Mar. Drugs 2018, 16(4), 128; https://doi.org/10.3390/md16040128 - 14 Apr 2018
Cited by 4 | Viewed by 4743
Abstract
As an important glycosaminoglycan, keratan sulfate (KS) mainly exists in corneal and cartilage, possessing various biological activities. In this study, we purified KS from blue shark (Prionace glauca) cartilage and prepared KS oligosaccharides (KSO) through keratanase II-catalyzed hydrolysis. The structures of [...] Read more.
As an important glycosaminoglycan, keratan sulfate (KS) mainly exists in corneal and cartilage, possessing various biological activities. In this study, we purified KS from blue shark (Prionace glauca) cartilage and prepared KS oligosaccharides (KSO) through keratanase II-catalyzed hydrolysis. The structures of KS and KSO were characterized using multi-dimensional nuclear magnetic resonance (NMR) spectra and liquid chromatography-mass spectrometry (LC-MS). Shark cartilage KS was highly sulfated and modified with ~2.69% N-acetylneuraminic acid (NeuAc) through α(2,3)-linked to galactose. Additionally, KS exhibited binding affinity to Ricinus communis agglutinin I (RCA120) in a concentration-dependent manner, a highly toxic lectin from beans of the castor plant. Furthermore, KSO from dp2 to dp8 bound to RCA120 in the increasing trend while the binding affinity of dp8 was superior to polysaccharide. These results define novel structural features for KS from Prionace glauca cartilage and demonstrate the potential application on ricin-antidote exploitation. Full article
(This article belongs to the Special Issue Marine Drugs Interact with Functional Proteins)
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16 pages, 2140 KiB  
Article
Functional Expression and Characterization of the Recombinant N-Acetyl-Glucosamine/N-Acetyl-Galactosamine-Specific Marine Algal Lectin BPL3
by Hyun-Ju Hwang, Jin-Woo Han, Gwang Hoon Kim and Jong Won Han
Mar. Drugs 2018, 16(1), 13; https://doi.org/10.3390/md16010013 - 05 Jan 2018
Cited by 6 | Viewed by 4429
Abstract
Lectins, characterized by their carbohydrate-binding ability, have extensive practical applications. However, their industrial use is limited due to impurity. Thus, quality-controlled production of recombinant lectin is necessary. In this study, the algal lectin BPL3 (Bryopsis plumosa lectin 3) was successfully produced using [...] Read more.
Lectins, characterized by their carbohydrate-binding ability, have extensive practical applications. However, their industrial use is limited due to impurity. Thus, quality-controlled production of recombinant lectin is necessary. In this study, the algal lectin BPL3 (Bryopsis plumosa lectin 3) was successfully produced using a bacterial expression system, BL21(DE3), with an artificial repeated structure (dimeric construct). Recombinant dimeric BPL3 (rD2BPL3) was confirmed by LC-MS/MS spectrometry. Expression efficiency was greater for the construct with the repeat structure (rD2BPL3) than the monomeric form (rD1BPL3). Optimal conditions for expression were 1 mM IPTG at 20 °C. Recombinant lectin was purified under denaturing conditions and refolded by the flash dilution method. Recombinant BPL3 was solubilized in 1× PBS containing 2 M urea. rD2BPL3 showed strong hemagglutination activity using human erythrocyte. rD2BPL3 had a similar sugar specificity to that of the native protein, i.e., to N-acetyl-glucosamine (GlcNAc) and N-acetyl-galactosamine (GalNAc). Glycan array results showed that recombinant BPL3 and native BPL3 exhibited different binding properties. Both showed weak binding activity to α-Man-Sp. Native BPL3 showed strong binding specificity to the alpha conformation of amino sugars, and rD2BPL3 had binding activity to the beta conformation. The process developed in this study was suitable for the quality-controlled large-scale production of recombinant lectins. Full article
(This article belongs to the Special Issue Marine Drugs Interact with Functional Proteins)
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Review

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21 pages, 1830 KiB  
Review
Molecular Targets of Active Anticancer Compounds Derived from Marine Sources
by Xiaoping Song, Ying Xiong, Xin Qi, Wei Tang, Jiajia Dai, Qianqun Gu and Jing Li
Mar. Drugs 2018, 16(5), 175; https://doi.org/10.3390/md16050175 - 22 May 2018
Cited by 25 | Viewed by 5068
Abstract
Over the past decades, a number of novel compounds, which are produced in the marine environment, have been found to exhibit the anticancer effects. This review focuses on molecular targets of marine-derived anticancer candidates in clinical and preclinical studies. They are kinases, transcription [...] Read more.
Over the past decades, a number of novel compounds, which are produced in the marine environment, have been found to exhibit the anticancer effects. This review focuses on molecular targets of marine-derived anticancer candidates in clinical and preclinical studies. They are kinases, transcription factors, histone deacetylase, the ubiquitin-proteasome system, and so on. Specific emphasis of this review paper is to provide information on the optimization of new target compounds for future research and development of anticancer drugs, based on the identification of structures of these target molecules and parallel compounds. Full article
(This article belongs to the Special Issue Marine Drugs Interact with Functional Proteins)
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