Strong inhibitory activities and action modes of lipopeptides on lipase.
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ABSTRACT:
SUBMITTER: Chen MC
PROVIDER: S-EPMC7170388 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In late December 2019, a novel coronavirus, namely severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), escaped the animal-human interface and emerged as an ongoing global pandemic with severe flu-like illness, commonly known as coronavirus disease 2019 (COVID-19). In this study, a molecular docking study was carried out for seventeen (17) structural analogues prepared from natural maslinic and oleanolic acids, screened against SARS-CoV-2 main protease. Furthermore, we experimentally validated the virtual data by measuring the half-maximal cytotoxic and inhibitory concentrations of each compound. Interestingly, the chlorinated isoxazole linked maslinic acid (compound 17) showed promising antiviral activity at micromolar non-toxic concentrations. Thoughtfully, we showed that compound 17 mainly impairs the viral replication of SARS-CoV-2. Furthermore, a very promising SAR study for the examined compounds was concluded, which could be used by medicinal chemists in the near future for the design and synthesis of potential anti-SARS-CoV-2 candidates. Our results could be very promising for performing further additional in vitro and in vivo studies on the tested compound (17) before further licensing for COVID-19 treatment.
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Project description:Since 2016, the invasive halophyte Spartina anglica has been colonizing mudflats along the western coast of South Korea. In order to minimize costs on S. anglica expansion management and waste-treatment of collected biomass, the potential application of the collected biomass of S. anglica was investigated. Ethanolic extracts and subfractions thereof (hexanes, methylene chloride, ethyl acetate, 1-butanol, and water-soluble) of the aerial and belowground parts of S. anglica showed free radical-scavenging [2,2-diphenyl-1-picrylhydrazyl (DPPH), and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS)], tyrosinase inhibitory, and pancreatic lipase inhibitory activities. An ethyl acetate fraction derived from aerial parts (EA-a) showed the most potent radical-scavenging and pancreatic lipase inhibitory activities, whereas tyrosinase inhibition was mainly observed in the methylene chloride soluble fractions (MC-bg) and other lipophilic fractions (ethyl acetate and hexanes layers) obtained from belowground parts. The major EA-a compound isolated and identified was 1,3-di-O-trans-feruloyl quinic acid (1) based on spectroscopic analysis, whereas the two major MC-bg compounds were identified as p-hydroxybenzaldehyde (2) and N-trans-feruloyltyramine (3). Compounds 1 and 3 scavenged both DPPH and ABTS radicals, whereas 1 and 2 inhibited pancreatic lipase activity. These results indicate that extracts and fractions of S. anglica have antioxidant, anti-obesity, and whitening properties with potential pharmaceutical, cosmeceutical, and functional food applications.
| S-EPMC7914639 | biostudies-literature
Project description:The extraordinary hypolipidemic effects of polyphenolic compounds from tea have been confirmed in our previous study. To gain compounds with more potent activities, using the conformations of the most active compound revealed by molecular docking, a 3D-QSAR pancreatic lipase inhibitor model with good predictive ability was established and validated by CoMFA and CoMISA methods. With good statistical significance in CoMFA (r2cv = 0.622, r2 = 0.956, F = 261.463, SEE = 0.096) and CoMISA (r2cv = 0.631, r2 = 0.932, F = 75.408, SEE = 0.212) model, we summarized the structure-activity relationship between polyphenolic compounds and pancreatic lipase inhibitory activities and find the bulky substituents in R2, R4 and R5, hydrophilic substituents in R1 and electron withdrawing groups in R2 are the key factors to enhance the lipase inhibitory activities. Under the guidance of the 3D-QSAR results, (2R,3R,2'R,3'R)-desgalloyloolongtheanin-3,3'-O-digallate (DOTD), a potent lipase inhibitor with an IC50 of 0.08 μg/ml, was obtained from EGCG oxidative polymerization catalyzed by crude polyphenol oxidase. Furthermore, DOTD was found to inhibit lipid absorption in olive oil-loaded rats, which was related with inhibiting the activities of lipase in the intestinal mucosa and contents.
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Project description:This study investigated the antimicrobial activities and modes of action of penta-, hexa-, hepta-, octa-, nona-, and deca-O-galloylglucose (gallotannins) isolated from mango kernels. The MICs and minimum bactericidal concentrations (MBCs) against food-borne bacteria and fungi were determined using a critical dilution assay. Gram-positive bacteria were generally more susceptible to gallotannins than were Gram-negative bacteria. The MICs of gallotannins against Bacillus subtilis, Bacillus cereus, Clostridium botulinum, Campylobacter jejuni, Listeria monocytogenes, and Staphylococcus aureus were 0.2 g liter(-1) or less; enterotoxigenic Escherichia coli and Salmonella enterica were inhibited by 0.5 to 1 g liter(-1), and lactic acid bacteria were resistant. The use of lipopolysaccharide mutants of S. enterica indicated that the outer membrane confers resistance toward gallotannins. Supplementation of LB medium with iron eliminated the inhibitory activity of gallotannins against Staphylococcus aureus, and siderophore-deficient mutants of S. enterica were less resistant toward gallotannins than was the wild-type strain. Hepta-O-galloylglucose sensitized Lactobacillus plantarum TMW1.460 to hop extract, indicating inactivation of hop resistance mechanisms, e.g., the multidrug resistance (MDR) transporter HorA. Carbohydrate metabolism of Lactococcus lactis MG1363, a conditionally respiring organism, was influenced by hepta-O-galloylglucose when grown under aerobic conditions and in the presence of heme but not under anaerobic conditions, indicating that gallotannins influence the respiratory chain. In conclusion, the inhibitory activities of gallotannins are attributable to their strong affinity for iron and likely additionally relate to the inactivation of membrane-bound proteins.
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Project description:A preceding experiment suggested that a compound, which inhibits binding of the REST/NRSF segment to the cleft of a receptor protein mSin3B, can be a potential drug candidate to ameliorate many neuropathies. We have recently developed an enhanced conformational sampling method, genetic-algorithm-guided multi-dimensional virtual-system-coupled canonical molecular dynamics, and in the present study, applied it to three systems consisting of mSin3B and one of three compounds, sertraline, YN3, and acitretin. Other preceding experiments showed that only sertraline inhibits the binding of REST/NRSF to mSin3B. The current simulation study produced the spatial distribution of the compounds around mSin3B, and showed that sertraline and YN3 bound to the cleft of mSin3B with a high propensity, although acitretin did not. Further analyses of the simulation data indicated that only the sertraline-mSin3B complex produced a hydrophobic core similar to that observed in the molecular interface of the REST/NRSF-mSin3B complex: An aromatic ring of sertraline sunk deeply in the mSin3B's cleft forming a hydrophobic core contacting to hydrophobic amino-acid residues located at the bottom of the cleft. The present study proposes a step to design a compound that inhibits competitively the binding of a ligand to its receptor.
| S-EPMC7971087 | biostudies-literature
Project description:BackgroundTraditional folk medicinal plants have recently become popular and are widely used for primary health care. Since Thailand has a great diversity of indigenous (medicinal) plant species, this research investigated 52 traditionally used species of Thai medicinal plants for their in vitro cytotoxic, antioxidant, lipase inhibitory and antimicrobial activities.MethodsThe 55 dried samples, derived from the medicinally used parts of the 52 plant species were sequentially extracted by hexane, dichloromethane, ethanol and water. These 220 extracts were then screened for in vitro (i) cytotoxicity against four cell lines, derived from human lung (A549), breast (MDA-MB-231), cervical (KB3-1) and colon (SW480) cancers, using the MTT cytotoxicity assay; (ii) antioxidant activity, analyzed by measuring the scavenging activity of DPPH radicals; (iii) lipase inhibitory activity, determined from the hydrolytic reaction of p-nitrophenyllaurate with pancreatic lipase; and (iv) antimicrobial activity against three Gram-positive and two Gram-negative bacteria species plus one strain of yeast using the disc-diffusion method and determination of the minimum inhibitory concentration by the broth micro-dilution assay.ResultsThe crude dichloromethane and/or ethanol extracts from four plant species showed an effective in vitro cytotoxic activity against the human cancer cell lines that was broadly similar to that of the specific chemotherapy drugs (etoposide, doxorubicin, vinblastine and oxaliplatin). In particular, this is the first report of the strong in vitro cytotoxic activity of Bauhinia strychnifolia vines. The tested tissue parts of only six plant species (Allium sativum, Cocoloba uvifera, Dolichandrone spathacea, Lumnitzera littorea, Sonneratia alba and Sonneratia caseolaris) showed promising potential antioxidant activity, whereas lipase inhibitory activity was only found in the ethanol extract from Coscinum fenestratum and this was weak at 17-fold lower than Orlistat, a known lipase inhibitor. The highest antimicrobial activity was observed in the extracts from S. alba and S. caseolaris against Pseudomonas aeruginosa and Candida albicans, respectively.ConclusionThe Thai medicinal plant B. strychnifolia is first reported to exert strong in vitro cytotoxic activities against human cancer cell lines and warrants further enrichment and characterization. The broad spectrum of the biological activities from the studied plant extracts can be applied as the guideline for the selection of Thai medicinal plant species for further pharmacological and phytochemical investigations.
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Project description:Oxidative stress and obesity are critical risk factors for metabolic syndrome. The consumption of functional food ingredients can a viable strategy to alleviate oxidative stress and obesity. In this study, the hydro-ethanolic extract of the edible insect Polyrhachis vicina was prepared and its bioactive components were characterized. The total polyphenol contents, total flavonoid contents, antioxidant and pancreatic lipase (PL) inhibitory activities of the extract were determined in vitro. In total, 60 bioactive components were tentatively identified in the P. vicina extract. Polyphenols and fatty acids were further quantified using LC-MS and GC-MS, respectively. P. vicina extract possessed excellent antioxidant and PL inhibition activities. Salicylic acid, gallic acid, liquiritigenin, and naringenin, which were the major polyphenols in the P. vicina extract, interacted with PL through hydrogen bonding, hydrophilic or hydrophobic and pi-cation interactions. Thus, P. vicina extract can be used as a nutraceutical to alleviate oxidative stress-induced disease and manage obesity.
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Project description:BackgroundThe emerging zoonotic paramyxovirus Nipah virus (NiV) causes severe respiratory and neurological disease in humans, with high fatality rates. Nipah virus can be transmitted via person-to-person contact, posing a high risk for epidemic outbreaks. However, a broadly applicable approach for human NiV outbreaks in field settings is lacking.MethodsWe engineered new antiviral lipopeptides and analyzed in vitro fusion inhibition to identify an optimal candidate for prophylaxis of NiV infection in the lower respiratory tract, and we assessed antiviral efficiency in 2 different animal models.ResultsWe show that lethal NiV infection can be prevented with lipopeptides delivered via the respiratory route in both hamsters and nonhuman primates. By targeting retention of peptides for NiV prophylaxis in the respiratory tract, we avoid its systemic delivery in individuals who need only prevention, and thus we increase the safety of treatment and enhance utility of the intervention.ConclusionsThe experiments provide a proof of concept for the use of antifusion lipopeptides for prophylaxis of lethal NiV. These results advance the goal of rational development of potent lipopeptide inhibitors with desirable pharmacokinetic and biodistribution properties and a safe effective delivery method to target NiV and other pathogenic viruses.
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| S-EPMC7015741 | biostudies-literature
Project description:Propagation of light beams through scattering or multimode systems may lead to the randomization of the spatial coherence of the light. Although information is not lost, its recovery requires a coherent interferometric reconstruction of the original signals, which have been scrambled into the modes of the scattering system. Here we show that we can automatically unscramble optical beams that have been arbitrarily mixed in a multimode waveguide, undoing the scattering and mixing between the spatial modes through a mesh of silicon photonics tuneable beam splitters. Transparent light detectors integrated in a photonic chip are used to directly monitor the evolution of each mode along the mesh, allowing sequential tuning and adaptive individual feedback control of each beam splitter. The entire mesh self-configures automatically through a progressive tuning algorithm and resets itself after significantly perturbing the mixing, without turning off the beams. We demonstrate information recovery by the simultaneous unscrambling, sorting and tracking of four mixed modes, with residual cross-talk of -20?dB between the beams. Circuit partitioning assisted by transparent detectors enables scalability to meshes with a higher port count and to a higher number of modes without a proportionate increase in the control complexity. The principle of self-configuring and self-resetting in optical systems should be applicable in a wide range of optical applications.
| S-EPMC6062024 | biostudies-literature