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Enzyme Inhibitors from Marine Resources

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A special issue of Marine Drugs (ISSN 1660-3397). This special issue belongs to the section "Marine Pharmacology".

Deadline for manuscript submissions: closed (29 February 2024) | Viewed by 23034

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Prof. Dr. Francesc Xavier Avilés

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Institute for Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Campus Universitari, Bellaterra, Cerdanyola del Vallès, 08193 Barcelona, Spain
Interests: proteolytic enzymes and inhibitors; natural/synthetic inhibitors and ligands; structure-function; proteomics; molecular imaging; drug-discovery and screening.

Prof. Dr. Isel Pascual

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Guest Editor

Centre for Protein Studies, Faculty of Biology, University of Havana, Cuba, calle 25, Nº 455 (Vedado), La Habana, Cuba
Interests: aminopeptidases and inhibitors; natural and synthetic inhibitors; cancer; malaria; drug-discovery and screening.

Special Issue Information

Dear Colleagues,

Marine living organisms and their main and secondary compounds and metabolites are among the richest in biological diversity. Many of their fundamental qualities and aplications are still fully or partially unexplored. Given that enzymes are essential in the plethora of biological functions of these organisms, enzyme inhibitors are also involved in the control of these functions, as well as in many diseases and attack–defence processes. Research on the natural inhibitors found in marine organisms is, therefore, of great interest nowadays in a myriad of research perspectives.

The present Special Issue intends to collect novel research on non-peptide or peptide/protein inhibitors, or derived forms, with focus on the isolation, structure–function characterization, method of action, variety, evolution, screening, genomics–proteomics, and classification of marine enzyme inhibitors. Additionally, we wish to dosument their behaviour in normal, diseased, and perturbed (i.e., extreme or stressed) conditions, as well as in attack–defence states and the interrelationships among organisms. Related research on organisms from large vertebrates and algae to small invertebrates and microorganisms is encouraged. Additionally, studies on the potential value of such molecules for biological, biotechnological, and pharmaceutical/biomedical uses, particularly as drugs or lead compounds against microbial, viral, parasitic, inflammatory, cardio-vascular, and oncological diseases, are welcome. Reviews on successes and central issues will also be acknowledged.

Prof. Dr. Francesc Xavier Avilés
Prof. Dr. Isel Pascual
Guest Editors

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 inhibitors of enzymes
non-peptide and peptide/protein inhibitors
isolation and characterization
structure-function
genomics and proteomics
variety and evolution
biological role
biotechnology
drug screening and discovery
imaging and nano-technology
potential for therapeutics

Published Papers (10 papers)

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Research

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11 pages, 1045 KiB

Open AccessArticle

Purification and Molecular Docking Study on the Angiotensin I-Converting Enzyme (ACE)-Inhibitory Peptide Isolated from Hydrolysates of the Deep-Sea Mussel Gigantidas vrijenhoeki

by Seong-Yeong Heo, Nalae Kang, Eun-A Kim, Junseong Kim, Seung-Hong Lee, Ginnae Ahn, Je Hyeok Oh, A Young Shin, Dongsung Kim and Soo-Jin Heo

Mar. Drugs 2023, 21(8), 458; https://doi.org/10.3390/md21080458 - 21 Aug 2023

Cited by 1 | Viewed by 1058

Abstract

The objective of this study was to prepare an angiotensin I-converting enzyme (ACE)-inhibitory peptide from the hydrothermal vent mussel, Gigantidas vrijenhoeki. The G. vrijenhoeki protein was hydrolyzed by various hydrolytic enzymes. The peptic hydrolysate exhibited the highest ACE-inhibitory activity and was fractionated into four molecular weight ranges by ultrafiltration. The <1 kDa fraction exhibited the highest ACE inhibitory activity and was found to have 11 peptide sequences. Among the analyzed peptides, KLLWNGKM exhibited stronger ACE inhibitory activity and an IC₅₀ value of 0.007 μM. To investigate the ACE-inhibitory activity of the analyzed peptides, a molecular docking study was performed. KLLWNGKM exhibited the highest binding energy (−1317.01 kcal/mol), which was mainly attributed to the formation of hydrogen bonds with the ACE active pockets, zinc-binding motif, and zinc ion. These results indicate that G. vrijenhoeki-derived peptides can serve as nutritional and pharmacological candidates for controlling blood pressure. Full article

(This article belongs to the Special Issue Enzyme Inhibitors from Marine Resources)

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15 pages, 1355 KiB

Open AccessArticle

Generation of Bioactive Peptides from Porphyridium sp. and Assessment of Their Potential for Use in the Prevention of Hypertension, Inflammation and Pain

by Maria Hayes, Rotimi E. Aluko, Elena Aurino and Leticia Mora

Mar. Drugs 2023, 21(8), 422; https://doi.org/10.3390/md21080422 - 25 Jul 2023

Cited by 1 | Viewed by 1415

Abstract

Inflammation, hypertension, and negative heart health outcomes including cardiovascular disease are closely linked but the mechanisms by which inflammation can cause high blood pressure are not yet fully elucidated. Cyclooxygenase (COX) enzymes play a role in pain, inflammation, and hypertension development, and inhibition of these enzymes is currently of great interest to researchers and pharmaceutical companies. Non-steroidal anti-inflammatory drugs are the drug of choice in terms of COX inhibition but can have negative side effects for consumers. Functional food ingredients containing cyclooxygenase inhibitors offer a strategy to inhibit cyclooxygenases without negative side effects. Several COX inhibitors have been discovered, to date, from marine and other resources. We describe here, for the first time, the generation and characterization of a bioactive hydrolysate generated using Viscozyme^® and Alcalase from the red microalga Porphyridium sp. The hydrolysate demonstrates in vitro COX-1 inhibitory activity and antihypertensive activity in vivo, assessed using spontaneously hypertensive rats (SHRs). Peptides were identified and sequenced using MS and assessed using an in silico computational approach for potential bioactivities. The peptides predicted to be bioactive, including GVDYVRFF, AIPAAPAAPAGPKLY, and LIHADPPGVGL were chemically synthesized and cyclooxygenase inhibition was confirmed. Peptides AIPAAPAAPAGPKLY and LIHADPPGVGL had COX-1 IC₅₀ values of 0.2349 mg/mL (0.16 µM) and 0.2193 mg/mL (0.2 µM), respectively. The hydrolysate was included in a food carrier (jelly candies) and an antihypertensive effect was observed in SHRs. Full article

(This article belongs to the Special Issue Enzyme Inhibitors from Marine Resources)

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17 pages, 3164 KiB

Open AccessArticle

Isolation and Characterization of NpCI, a New Metallocarboxypeptidase Inhibitor from the Marine Snail Nerita peloronta with Anti-Plasmodium falciparum Activity

by Aymara Cabrera-Muñoz, Yusvel Sierra-Gómez, Giovanni Covaleda-Cortés, Mey L. Reytor, Yamile González-González, José M. Bautista, Francesc Xavier Avilés and Maday Alonso-del-Rivero

Mar. Drugs 2023, 21(2), 94; https://doi.org/10.3390/md21020094 - 28 Jan 2023

Cited by 1 | Viewed by 1407

Abstract

Metallocarboxypeptidases are zinc-dependent peptide-hydrolysing enzymes involved in several important physiological and pathological processes. They have been a target of growing interest in the search for natural or synthetic compound binders with biomedical and drug discovery purposes, i.e., with potential as antimicrobials or antiparasitics. Given that marine resources are an extraordinary source of bioactive molecules, we screened marine invertebrates for new inhibitory compounds with such capabilities. In this work, we report the isolation and molecular and functional characterization of NpCI, a novel strong metallocarboxypeptidase inhibitor from the marine snail Nerita peloronta. NpCI was purified until homogeneity using a combination of affinity chromatography and RP-HPLC. It appeared as a 5921.557 Da protein with 53 residues and six disulphide-linked cysteines, displaying a high sequence similarity with NvCI, a carboxypeptidase inhibitor isolated from Nerita versicolor, a mollusc of the same genus. The purified inhibitor was determined to be a slow- and tight-binding inhibitor of bovine CPA (Ki = 1.1·× 10⁻⁸ mol/L) and porcine CPB (Ki = 8.15·× 10⁻⁸ mol/L) and was not able to inhibit proteases from other mechanistic classes. Importantly, this inhibitor showed antiplasmodial activity against Plasmodium falciparum in an in vitro culture (IC₅₀ = 5.5 μmol/L), reducing parasitaemia mainly by inhibiting the later stages of the parasite’s intraerythrocytic cycle whilst having no cytotoxic effects on human fibroblasts. Interestingly, initial attempts with other related proteinaceous carboxypeptidase inhibitors also displayed similar antiplasmodial effects. Coincidentally, in recent years, a metallocarboxypeptidase named PfNna1, which is expressed in the schizont phase during the late intraerythrocytic stage of the parasite’s life cycle, has been described. Given that NpCI showed a specific parasiticidal effect on P. falciparum, eliciting pyknotic/dead parasites, our results suggest that this and related inhibitors could be promising starting agents or lead compounds for antimalarial drug discovery strategies. Full article

(This article belongs to the Special Issue Enzyme Inhibitors from Marine Resources)

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18 pages, 3108 KiB

Open AccessArticle

Effect of Phlorotannins from Brown Algae Costaria costata on α-N-Acetylgalactosaminidase Produced by Duodenal Adenocarcinoma and Melanoma Cells

by Irina Bakunina, Tatiana Imbs, Galina Likhatskaya, Valeria Grigorchuk, Anastasya Zueva, Olesya Malyarenko and Svetlana Ermakova

Mar. Drugs 2023, 21(1), 33; https://doi.org/10.3390/md21010033 - 30 Dec 2022

Cited by 2 | Viewed by 1445

Abstract

The inhibitor of human α-N-acetylgalactosaminidase (α-NaGalase) was isolated from a water–ethanol extract of the brown algae Costaria costata. Currently, tumor α-NaGalase is considered to be a therapeutic target in the treatment of cancer. According to NMR spectroscopy and mass spectrometric analysis, it is a high-molecular-weight fraction of phlorethols with a degree of polymerization (DP) equaling 11–23 phloroglucinols (CcPh). It was shown that CcPh is a direct inhibitor of α-NaGalases isolated from HuTu 80 and SK-MEL-28 cells (IC₅₀ 0.14 ± 0.008 and 0.12 ± 0.004 mg/mL, respectively) and reduces the activity of this enzyme in HuTu 80 and SK-MEL-28 cells up to 50% at concentrations of 15.2 ± 9.5 and 5.7 ± 1.6 μg/mL, respectively. Molecular docking of the putative DP-15 oligophlorethol (P15OPh) and heptaphlorethol (PHPh) with human α-NaGalase (PDB ID 4DO4) showed that this compound forms a complex and interacts directly with the Asp 156 and Asp 217 catalytic residues of the enzyme in question. Thus, brown algae phlorethol CcPh is an effective marine-based natural inhibitor of the α-NaGalase of cancer cells and, therefore, has high therapeutic potential. Full article

(This article belongs to the Special Issue Enzyme Inhibitors from Marine Resources)

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14 pages, 1798 KiB

Open AccessArticle

Rapid Mining of Novel α-Glucosidase and Lipase Inhibitors from Streptomyces sp. HO1518 Using UPLC-QTOF-MS/MS

by Jianlin Xu, Zhifeng Liu, Zhanguang Feng, Yuhong Ren, Haili Liu and Yong Wang

Mar. Drugs 2022, 20(3), 189; https://doi.org/10.3390/md20030189 - 04 Mar 2022

Cited by 2 | Viewed by 2396

Abstract

A rapid and sensitive method using ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS/MS) was applied for the analysis of the metabolic profile of acarviostatin-containing aminooligosaccharides derived from Streptomyces sp. HO1518. A total of ninety-eight aminooligosaccharides, including eighty potential new compounds, were detected mainly based on the characteristic fragment ions originating from quinovosidic bond cleavages in their molecules. Following an LC-MS-guided separation technique, seven new aminooligosaccharides (10–16) along with four known related compounds (17–20) were obtained directly from the crude extract of strain HO1518. Compounds 10–13 represent the first examples of aminooligosaccharides with a rare acarviostatin II02-type structure. In addition, all isolates displayed considerable inhibitory effects on three digestive enzymes, which revealed that the number of the pseudo-trisaccharide core(s), the feasible length of the oligosaccharides, and acyl side chain exerted a crucial influence on their bioactivities. These results demonstrated that the UPLC-QTOF-MS/MS-based metabolomics approach could be applied for the rapid identification of aminooligosaccharides and other similar structures in complex samples. Furthermore, this study highlights the potential of acylated aminooligosaccharides with conspicuous α-glucosidase and lipase inhibition for the future development of multi-target anti-diabetic drugs. Full article

(This article belongs to the Special Issue Enzyme Inhibitors from Marine Resources)

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22 pages, 4599 KiB

Open AccessArticle

Optimized Degradation and Inhibition of α-glucosidase Activity by Gracilaria lemaneiformis Polysaccharide and Its Production In Vitro

by Xiaoshan Long, Xiao Hu, Shaobo Zhou, Huan Xiang, Shengjun Chen, Laihao Li, Shucheng Liu and Xianqing Yang

Mar. Drugs 2022, 20(1), 13; https://doi.org/10.3390/md20010013 - 22 Dec 2021

Cited by 10 | Viewed by 2861

Abstract

Gracilaria lemaneiformis polysaccharide (GLP) exhibits good physiological activities, and it is more beneficial as it is degraded. After its degradation by hydrogen peroxide combined with vitamin C (H₂O₂-Vc) and optimized by Box–Behnken Design (BBD), a new product of GLP-HV will be generated. While using GLP as control, two products of GLP-H (H₂O₂-treated) and GLP-V (Vc-treated) were also produced. These products chemical characteristics (total sugar content, molecular weight, monosaccharide composition, UV spectrum, morphological structure, and hypolipidemic activity in vitro) were assessed. The results showed that the optimal conditions for H₂O₂-Vc degradation were as follows: H₂O₂-Vc concentration was 18.7 mM, reaction time was 0.5 h, and reaction temperature was 56 °C. The total sugar content of GLP and its degradation products (GLP-HV, GLP-H and GLP-V) were more than 97%, and their monosaccharides are mainly glucose and galactose. The SEM analysis demonstrated that H₂O₂-Vc made the structure loose and broken. Moreover, GLP, GLP-HV, GLP-H, and GLP-V had significantly inhibition effect on α-glucosidase, and their IC₅₀ value were 3.957, 0.265, 1.651, and 1.923 mg/mL, respectively. GLP-HV had the best inhibition effect on α-glucosidase in a dose-dependent manner, which was the mixed type of competitive and non-competitive. It had a certain quenching effect on fluorescence of α-glucosidase, which may be dynamic quenching. Full article

(This article belongs to the Special Issue Enzyme Inhibitors from Marine Resources)

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Review

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37 pages, 16948 KiB

Open AccessReview

Marine Invertebrates: A Promissory Still Unexplored Source of Inhibitors of Biomedically Relevant Metallo Aminopeptidases Belonging to the M1 and M17 Families

by Isel Pascual Alonso, Fabiola Almeida García, Mario Ernesto Valdés Tresanco, Yarini Arrebola Sánchez, Daniel Ojeda del Sol, Belinda Sánchez Ramírez, Isabelle Florent, Marjorie Schmitt and Francesc Xavier Avilés

Mar. Drugs 2023, 21(5), 279; https://doi.org/10.3390/md21050279 - 28 Apr 2023

Viewed by 4413

Abstract

Proteolytic enzymes, also known as peptidases, are critical in all living organisms. Peptidases control the cleavage, activation, turnover, and synthesis of proteins and regulate many biochemical and physiological processes. They are also involved in several pathophysiological processes. Among peptidases, aminopeptidases catalyze the cleavage of the N-terminal amino acids of proteins or peptide substrates. They are distributed in many phyla and play critical roles in physiology and pathophysiology. Many of them are metallopeptidases belonging to the M1 and M17 families, among others. Some, such as M1 aminopeptidases N and A, thyrotropin-releasing hormone-degrading ectoenzyme, and M17 leucyl aminopeptidase, are targets for the development of therapeutic agents for human diseases, including cancer, hypertension, central nervous system disorders, inflammation, immune system disorders, skin pathologies, and infectious diseases, such as malaria. The relevance of aminopeptidases has driven the search and identification of potent and selective inhibitors as major tools to control proteolysis with an impact in biochemistry, biotechnology, and biomedicine. The present contribution focuses on marine invertebrate biodiversity as an important and promising source of inhibitors of metalloaminopeptidases from M1 and M17 families, with foreseen biomedical applications in human diseases. The results reviewed in the present contribution support and encourage further studies with inhibitors isolated from marine invertebrates in different biomedical models associated with the activity of these families of exopeptidases. Full article

(This article belongs to the Special Issue Enzyme Inhibitors from Marine Resources)

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30 pages, 4881 KiB

Open AccessReview

Enzyme Inhibitors from Gorgonians and Soft Corals

by Andrea Córdova-Isaza, Sofía Jiménez-Mármol, Yasel Guerra and Emir Salas-Sarduy

Mar. Drugs 2023, 21(2), 104; https://doi.org/10.3390/md21020104 - 31 Jan 2023

Viewed by 1743

Abstract

For decades, gorgonians and soft corals have been considered promising sources of bioactive compounds, attracting the interest of scientists from different fields. As the most abundant bioactive compounds within these organisms, terpenoids, steroids, and alkaloids have received the highest coverage in the scientific literature. However, enzyme inhibitors, a functional class of bioactive compounds with high potential for industry and biomedicine, have received much less notoriety. Thus, we revised scientific literature (1974–2022) on the field of marine natural products searching for enzyme inhibitors isolated from these taxonomic groups. In this review, we present representative enzyme inhibitors from an enzymological perspective, highlighting, when available, data on specific targets, structures, potencies, mechanisms of inhibition, and physiological roles for these molecules. As most of the characterization studies for the new inhibitors remain incomplete, we also included a methodological section presenting a general strategy to face this goal by accomplishing STRENDA (Standards for Reporting Enzymology Data) project guidelines. Full article

(This article belongs to the Special Issue Enzyme Inhibitors from Marine Resources)

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28 pages, 3347 KiB

Open AccessReview

Computational Approaches to Enzyme Inhibition by Marine Natural Products in the Search for New Drugs

by Federico Gago

Mar. Drugs 2023, 21(2), 100; https://doi.org/10.3390/md21020100 - 30 Jan 2023

Cited by 4 | Viewed by 2894

Abstract

The exploration of biologically relevant chemical space for the discovery of small bioactive molecules present in marine organisms has led not only to important advances in certain therapeutic areas, but also to a better understanding of many life processes. The still largely untapped reservoir of countless metabolites that play biological roles in marine invertebrates and microorganisms opens new avenues and poses new challenges for research. Computational technologies provide the means to (i) organize chemical and biological information in easily searchable and hyperlinked databases and knowledgebases; (ii) carry out cheminformatic analyses on natural products; (iii) mine microbial genomes for known and cryptic biosynthetic pathways; (iv) explore global networks that connect active compounds to their targets (often including enzymes); (v) solve structures of ligands, targets, and their respective complexes using X-ray crystallography and NMR techniques, thus enabling virtual screening and structure-based drug design; and (vi) build molecular models to simulate ligand binding and understand mechanisms of action in atomic detail. Marine natural products are viewed today not only as potential drugs, but also as an invaluable source of chemical inspiration for the development of novel chemotypes to be used in chemical biology and medicinal chemistry research. Full article

(This article belongs to the Special Issue Enzyme Inhibitors from Marine Resources)

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15 pages, 1174 KiB

Open AccessReview

β-Lactams from the Ocean

by Jed F. Fisher and Shahriar Mobashery

Mar. Drugs 2023, 21(2), 86; https://doi.org/10.3390/md21020086 - 25 Jan 2023

Cited by 6 | Viewed by 2212

Abstract

The title of this essay is as much a question as it is a statement. The discovery of the β-lactam antibiotics—including penicillins, cephalosporins, and carbapenems—as largely (if not exclusively) secondary metabolites of terrestrial fungi and bacteria, transformed modern medicine. The antibiotic β-lactams inactivate essential enzymes of bacterial cell-wall biosynthesis. Moreover, the ability of the β-lactams to function as enzyme inhibitors is of such great medical value, that inhibitors of the enzymes which degrade hydrolytically the β-lactams, the β-lactamases, have equal value. Given this privileged status for the β-lactam ring, it is therefore a disappointment that the exemplification of this ring in marine secondary metabolites is sparse. It may be that biologically active marine β-lactams are there, and simply have yet to be encountered. In this report, we posit a second explanation: that the value of the β-lactam to secure an ecological advantage in the marine environment might be compromised by its close structural similarity to the β-lactones of quorum sensing. The steric and reactivity similarities between the β-lactams and the β-lactones represent an outside-of-the-box opportunity for correlating new structures and new enzyme targets for the discovery of compelling biological activities. Full article

(This article belongs to the Special Issue Enzyme Inhibitors from Marine Resources)

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