Spongionella Secondary Metabolites, Promising Modulators of Immune Response through CD147 Receptor Modulation

The modulation of the immune system can have multiple applications such as cancer treatment, and a wide type of processes involving inflammation where the potent chemotactic agent cyclophilin A (Cyp A) is implicated. The Porifera phylum, in which Spongionella is encompassed, is the main producer of marine bioactive compounds. Four secondary metabolites obtained from Spongionella (Gracilin H, A, L, and Tetrahydroaplysulphurin-1) were described to hit Cyp A and to block the release of inflammation mediators. Based on these results, some role of Spongionella compounds on other steps of the signaling pathway mediated by this chemotactic agent can be hypothesized. In the present paper, we studied the effect of these four compounds on the surface membrane CD147 receptor expression, on the extracellular levels of Cyp A and on the ability to migrate of concanavalin (Con A)-activated T lymphocytes. Similar to a well-known immunosuppressive agent cyclosporine A (CsA), Gracilin H, A, L, and tetrahydroaplysulphurin-1 were able to reduce the CD147 membrane expression and to block the release of Cyp A to the medium. Besides, by using Cyp A as chemotactic agent, T cell migration was inhibited when cells were previously incubated with Gracilin A and Gracilin L. These positive results lead us to test the in vivo effect of Gracilin H and L in a mouse ear delayed hypersensitive reaction. Thus, both compounds efficiently reduce the ear swelling as well as the inflammatory cell infiltration. These results provide more evidences for their potential therapeutic application in immune-related diseases of Spongionella compound

Structure-Based Design, Synthesis and Bioactivity of a New Anti-TNFα Cyclopeptide

As opposed to small molecules, macrocyclic peptides possess a large surface area and are recognised as promising candidates to selectively treat diseases by disrupting specific protein–protein interactions (PPIs). Due to the difficulty in predicting cyclopeptide conformations in solution, the de novo design of bioactive cyclopeptides remains significantly challenging. In this study, we used the combination of conformational analyses and molecular docking studies to design a new cyclopeptide inhibitor of the interaction between the human tumour necrosis factor alpha (TNFα) and its receptor TNFR-1. This interaction is a key in mediating the inflammatory response to tissue injury and infection in humans, and it is also an important causative factor of rheumatoid arthritis, psoriasis and inflammatory bowel disease. The solution state NMR structure of the cyclopeptide was determined, which helped to deduce its mode of interaction with TNFα. TNFα sensor cells were used to evaluate the biological activity of the peptide

A cell-based assay system for activators of the environmental cell stress response

This work was funded by The Scottish Government Rural and Environment Science and Analytical Services Division (RESAS), Scotland, United Kingdom and the Biotechnology and Biological Sciences Research Council (BBSRC; East-Bio Doctoral Training Partnership), United Kingdom. The funders had no role in the design of the study, the analysis and interpretation of the data, or the publication process. The authors wish to thank Prof. John Hayes, University of Dundee, for the NQO1-luciferase construct and Prof. Gary Felsenfeld, NIH, Bethesda for the plasmid pJC13-1.Peer reviewedPostprin

Spongionella secondary metabolites protect mitochondrial function in cortical neurons against oxidative stress

Accepted: 8 January 2014 This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Acknowledgments The research leading to these results has received funding from the following FEDER cofunded-grants: From Ministerio de Ciencia y Tecnología, Spain: AGL2009-13581-CO2-01, AGL2012-40485-CO2-01. From Xunta de Galicia, Spain: 10PXIB261254 PR. From the European Union’s Seventh Framework Programme managed by REA—Research Executive Agency (FP7/2007–2013) under grant agreement Nos. 265896 BAMMBO, 265409 µAQUA, and 262649 BEADS, 315285 CIGUATOOLS and 312184 PHARMASEA. From the Atlantic Area Programme (Interreg IVB Trans-national): 2009-1/117 Pharmatlantic. MER thanks the Government of the Arab Republic of Egypt for a PhD Scholarship. MJ thanks the Scottish University Life Science Alliance which provided funding to set up the compound library.Peer reviewedPublisher PD

The structural biology of patellamide biosynthesis

This work was supported by grants from the ERC339367 (JHN and MJ) and BBSRCBB/K015508/1 (JHN and MJ).The biosynthetic pathways for patellamide and related natural products have recently been studied by structural biology. These pathways produce molecules that have a complex framework and exhibit a diverse array of activity due to the variability of the amino acids that are found in them. As these molecules are difficult to synthesize chemically, exploitation of their properties has been modest. The patellamide pathway involves amino acid heterocyclization, peptide cleavage, peptide macrocyclization, heterocycle oxidation and epimerization; closely related products are also prenylated. Enzyme activities have been identified for all these transformations except epimerization, which may be spontaneous. This review highlights the recent structural and mechanistic work on amino acid heterocyclization, peptide cleavage and peptide macrocyclization. This work should help in using the enzymes to produce novel analogs of the natural products enabling an exploitation of their properties.Peer reviewe

Spongionella Secondary Metabolites Regulate Store Operated Calcium Entry Modulating Mitochondrial Functioning in SH-SY5Y Neuroblastoma Cells

cknowledgements The research leading to these results has received funding from the following FEDER cofounded-grants. From CDTI and Technological Funds, supported by Ministerio de Economía y Competitividad, AGL2012-40185-CO2-01, AGL2014-58210-R, and Consellería de Cultura, Educación e OrdenaciónUniversitaria, GRC2013-016, and through AxenciaGalega de Innovación, Spain, ITC-20133020 SINTOX. From CDTI under ISIP Programme, Spain, IDI-20130304 APTAFOOD. From the European Union's Seventh Framework Programme managed by REA - Research Executive Agency (FP7/2007-2013) under grant agreement 312184 PHARMASEA. Jon Andoni Sánchez is supported by a fellowship from Plan Galego de Investigación e Crecemento, Xunta de Galicia, Spain.Peer reviewedPublisher PD

A pyridinium derivative from Red Sea soft corals inhibited voltage-activated potassium conductances and increased excitability of rat cultured sensory neurones

BACKGROUND: Whole cell patch clamp recording and intracellular Ca(2+ )imaging were carried out on rat cultured dorsal root ganglion (DRG) neurones to characterize the actions of crude extracts and purified samples from Red Sea soft corals. The aim of the project was to identify compounds that would alter the excitability of DRG neurones. RESULTS: Crude extracts of Sarcophyton glaucum and Lobophyton crassum attenuated spike frequency adaptation causing DRG neurones to switch from firing single action potentials to multiple firing. The increase in excitability was associated with enhanced KCl-evoked Ca(2+ )influx. The mechanism of action of the natural products in the samples from the soft corals involved inhibition of voltage-activated K(+ )currents. An active component of the crude marine samples was identified as 3-carboxy-1-methyl pyridinium (trigonelline). Application of synthetic 3-carboxy-1-methyl pyridinium at high concentration (0.1 mM) also induced multiple firing and reduced voltage-activated K(+ )current. The changes in excitability of DRG neurones induced by 3-carboxy-1-methyl pyridinium suggest that this compound contributes to the bioactivity produced by the crude extracts from two soft corals. CONCLUSION: Sarcophyton glaucum and Lobophyton crassum contain natural products including 3-carboxy-1-methyl pyridinium that increase the excitability of DRG neurones. We speculate that in addition to developmental control and osmoregulation these compounds may contribute to chemical defenses

Structure of the cyanobactin oxidase ThcOx from Cyanothece sp. PCC 7425, the first structure to be solved at Diamond Light Source beamline I23 by means of S-SAD

Acknowledgements We thank Diamond Light Source for providing access to beamline I23. We also thank Thomas Sorensen and his staff for access to and support on beamline I02. This research was supported by grants from the UK Biotechnology and Biological Research Council (No. BB/K015508/1; JHN and MJ) and the European Research Council (No. 339367; JHN and MJ). Mass-spectrometric analysis was carried out by the Biomedical Sciences Research Complex Mass Spectrometry and Proteomics Facility, University of St Andrews and was funded by the Wellcome Trust (grant Nos. 094476/Z/10/Z and WT079272AIA). JHN is a Royal Society Wolfson Merit Award Holder and 1000 Talent scholar at Sichuan University.Peer reviewedPublisher PD

A synthetic cyclized antimicrobial peptide with potent effects against drug resistant skin pathogens

Acknowledgments We would like to thank Anna Blasi-Romero for helping with the set-up of the initial scanning electron microscopy experiments. This project was partially supported by the Stiftelsen Olle Engkvist Byggmästare (AB 186 678), Region Stockholm (AB, ALF project 995080), a fellowship grant from the EPSRC (no. EP/S027246/1, W.E.H.), the Bo Rydin Foundation (no. F30/20; NF), the Swedish Research Council (# no. 2011-3403; UG); and Postdoctoral scholarship by Elisabeth and Alfred Ahlqvists Stiftelse, Apotekarsocieteten (TM). The graphical abstract was created with a BioRender standard academic license.Peer reviewedPublisher PD

Structure of PatF from Prochloron didemni

Patellamides are macrocyclic peptides with potent biological effects and are a subset of the cyanobactins. Cyanobactins are natural products that are produced by a series of enzymatic transformations and a common modification is the addition of a prenyl group. Puzzlingly, the pathway for patellamides in Prochloron didemni contains a gene, patF, with homology to prenylases, but patellamides are not themselves prenylated. The structure of the protein PatF was cloned, expressed, purified and determined. Prenylase activity could not be demonstrated for the protein, and examination of the structure revealed changes in side-chain identity at the active site. It is suggested that these changes have inactivated the protein. Attempts to mutate these residues led to unfolded protein