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Gunasekera, Sunithi
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Mohotti, S., Rajendran, S., Muhammad, T., Strömstedt, A. A., Adhikari, A., Burman, R., . . . Gunasekera, S. (2019). Screening for bioactive secondary metabolites in Sri Lankan medicinal plants by microfractionation and targeted isolation of antimicrobial flavonoids from Derris scandens. Journal of Ethnopharmacology, 246, Article ID 112158.
Öppna denna publikation i ny flik eller fönster >>Screening for bioactive secondary metabolites in Sri Lankan medicinal plants by microfractionation and targeted isolation of antimicrobial flavonoids from Derris scandens
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2019 (Engelska)Ingår i: Journal of Ethnopharmacology, ISSN 0378-8741, E-ISSN 1872-7573, Vol. 246, artikel-id 112158Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Ethnopharmacological relevance: Sri Lanka is known to have very diverse flora. Many of these species are used for plant-based remedies, which form the integral part of two Sri Lankan systems of traditional medicine, Ayurveda and Deshiya Chikitsa. Despite their widespread use, only a limited number of studies have probed into the scientific evidence for bioactivity of these medicinal plants. Such studies rarely progress to the identification of bioactive natural products. Aim of the study: The primary aim was to develop a bioactivity screening method and apply it to 50 Sri Lankan medicinal plants where antimicrobial properties could be relevant for its traditional use. The subsequent aim was the progression into defining and characterising potent isolates within targeted compound classes from such plants, i.e. Derris scandens and its antimicrobial flavonoids. Material and methods: The plant collection comprised 24 species of Fabaceae, 15 Rubiaceae, 7 Solanaceae and 4 Cucurbitaceae plants. These 50 species were collected based on their ethnopharmacological importance and use in Sri Lankan traditional medicine. Crude extracts from each species were initially subjected to radial disc diffusion and microdilution assays. Subsequently, aqueous extracts of all plants were microfractionated in deep well plates using reversed-phase HPLC. Fractions were tested for antibacterial and cytotoxic activities and masses of target bioactive compounds were identified using mass spectrometry. Bioactive compounds with the masses identified through microfractions were isolated from Derris scandens using reversed-phase HPLC. The isolated pure compounds were characterised using LC-MS and NMR. Results: Crude aqueous extracts from 19 species showed activity against Gram-positive bacteria (Staphylococcus aureus and Bacillus cereus) in the radial disc diffusion assay. Crude aqueous extracts from 34 plant species and organic extracts from 46 plant species were active against S. aureus (<= 4 mg mL(-1)) in the microdilution assay. Microfractionation demonstrated antibacterial activity for 19 plants and cytotoxicity for 6 plants. Furthermore, target bioactive compounds and their molecular ions were identified during microfractionation. Dalpanitin and vicenin-3, two of the flavonoids isolated from Derris scandens gave MICs of 23 mu g mL(-1) against S. aureus. Dalpanitin also exhibited relevant MICs on Gram-negative bacteria (94 mu g mL(-1)) against Escherichia coli and Pseudomonas aeruginosa). Conclusion: The microfractionation protocol developed in this study enabled time-efficient screening of many plants species, using a small quantity of sample material. In addition, microfractionation served as a guiding tool for identifying individual antimicrobial compounds. Through this process, flavonoids were isolated from Derris scandens, out of which dalpanitin and vicenin-3 showed activity in the low micromolar range. The high hit rate for in vitro antibacterial properties from this ethnopharmacologically guided sample collection gives credence to Sri Lankan traditional herbal medicine as a source for drug discovery.

Nyckelord
Sri Lanka, Medicinal plants, Microfractionation, Antimicrobial activity, Cytotoxicity, Flavonoids
Nationell ämneskategori
Farmakologi och toxikologi
Identifikatorer
urn:nbn:se:uu:diva-397136 (URN)10.1016/j.jep.2019.112158 (DOI)000493211800010 ()31421182 (PubMedID)
Forskningsfinansiär
Vetenskapsrådet, 2013-06672
Tillgänglig från: 2019-11-28 Skapad: 2019-11-28 Senast uppdaterad: 2019-11-28Bibliografiskt granskad
Gunasekera, S., Muhammad, T., Strömstedt, A. A., Rosengren, K. J. & Göransson, U. (2018). Alanine and Lysine Scans of the LL-37-Derived Peptide Fragment KR-12 Reveal Key Residues for Antimicrobial Activity. ChemBioChem (Print), 19(9), 931-939
Öppna denna publikation i ny flik eller fönster >>Alanine and Lysine Scans of the LL-37-Derived Peptide Fragment KR-12 Reveal Key Residues for Antimicrobial Activity
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2018 (Engelska)Ingår i: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 19, nr 9, s. 931-939Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The human host defence peptide LL-37 is a broad-spectrum antibiotic with immunomodulatory functions. Residues 18-29 in LL-37 have previously been identified as a minimal peptide (KR-12) that retains antibacterial activity with decreased cytotoxicity. In this study, analogues of KR-12 were generated by Ala and Lys scans to identify key elements for activity. These were tested against a panel of human pathogens and for membrane permeabilisation on liposomes. Replacements of hydrophobic and cationic residues with Ala were detrimental for antibiotic potency. Substitutions by Lys increased activity, as long as the increase in cationic density did not disrupt the amphiphilic disposition of the helical structure. Importantly, substitutions showed differential effects against different organisms. Replacement of Gln5 with Lys and Asp9 with Ala or Lys improved the broad-spectrum activity most, each resulting in up to an eightfold increase in potency against Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans. The improved analogues displayed no significant toxicity against human cells, and thus, KR-12 is a tuneable template for antibiotic development.

Ort, förlag, år, upplaga, sidor
WILEY-V C H VERLAG GMBH, 2018
Nyckelord
antibiotics, cytotoxicity, drug discovery, peptides, structure-activity relationships
Nationell ämneskategori
Biokemi och molekylärbiologi
Identifikatorer
urn:nbn:se:uu:diva-356391 (URN)10.1002/cbic.201700599 (DOI)000431625100008 ()29430821 (PubMedID)
Forskningsfinansiär
Vetenskapsrådet, 2011-3403Carl Tryggers stiftelse för vetenskaplig forskning , CTS 10: 126Carl Tryggers stiftelse för vetenskaplig forskning , CTS 11: 169Svenska läkaresällskapet, SLS-254511
Tillgänglig från: 2018-07-25 Skapad: 2018-07-25 Senast uppdaterad: 2020-02-18Bibliografiskt granskad
Zumberge, J. A., Love, G. D., Cárdenas, P., Sperling, E. A., Gunasekera, S., Rohrssen, M., . . . Summons, R. E. (2018). Demosponge steroid biomarker 26-methylstigmastane provides evidence for Neoproterozoic animals. Nature Ecology & Evolution, 2(11), 1709-1714
Öppna denna publikation i ny flik eller fönster >>Demosponge steroid biomarker 26-methylstigmastane provides evidence for Neoproterozoic animals
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2018 (Engelska)Ingår i: Nature Ecology & Evolution, E-ISSN 2397-334X, Vol. 2, nr 11, s. 1709-1714Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Sterane biomarkers preserved in ancient sedimentary rocks hold promise for tracking the diversification and ecological expansion of eukaryotes. The earliest proposed animal biomarkers from demosponges (Demospongiae) are recorded in a sequence around 100 Myr long of Neoproterozoic-Cambrian marine sedimentary strata from the Huqf Supergroup, South Oman Salt Basin. This C-30 sterane biomarker, informally known as 24-isopropylcholestane (24-ipc), possesses the same carbon skeleton as sterols found in some modern-day demosponges. However, this evidence is controversial because 24-ipc is not exclusive to demosponges since 24-ipc sterols are found in trace amounts in some pelagophyte algae. Here, we report a new fossil sterane biomarker that co-occurs with 24-ipc in a suite of late Neoproterozoic-Cambrian sedimentary rocks and oils, which possesses a rare hydrocarbon skeleton that is uniquely found within extant demosponge taxa. This sterane is informally designated as 26-methylstigmastane (26-mes), reflecting the very unusual methylation at the terminus of the steroid side chain. It is the first animal-specific sterane marker detected in the geological record that can be unambiguously linked to precursor sterols only reported from extant demosponges. These new findings strongly suggest that demosponges, and hence multicellular animals, were prominent in some late Neoproterozoic marine environments at least extending back to the Cryogenian period.

Ort, förlag, år, upplaga, sidor
NATURE PUBLISHING GROUP, 2018
Nationell ämneskategori
Evolutionsbiologi
Identifikatorer
urn:nbn:se:uu:diva-370005 (URN)10.1038/s41559-018-0676-2 (DOI)000447964800013 ()30323207 (PubMedID)
Forskningsfinansiär
EU, Horisont 2020, 679849
Tillgänglig från: 2019-01-07 Skapad: 2019-01-07 Senast uppdaterad: 2019-01-07Bibliografiskt granskad
Wang, Y., Lloyd, K. A., Gunasekera, S., Eriksson, C., Ramsköld, D., Lundberg, K., . . . Grönwall, C. (2018). Repertoire Studies in Rheumatoid Arthritis Reveal B-Cell Distortions and Baseline Shifts in Unmutated IgG. Arthritis & Rheumatology, 70
Öppna denna publikation i ny flik eller fönster >>Repertoire Studies in Rheumatoid Arthritis Reveal B-Cell Distortions and Baseline Shifts in Unmutated IgG
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2018 (Engelska)Ingår i: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 70Artikel i tidskrift, Meeting abstract (Övrigt vetenskapligt) Published
Ort, förlag, år, upplaga, sidor
John Wiley & Sons, 2018
Nationell ämneskategori
Reumatologi och inflammation
Identifikatorer
urn:nbn:se:uu:diva-369631 (URN)000447268900009 ()
Tillgänglig från: 2018-12-17 Skapad: 2018-12-17 Senast uppdaterad: 2018-12-17Bibliografiskt granskad
Gunasekera, S., Fernandes-Cerqueira, C., Wennmalm, S., Wahamaa, H., Sommarin, Y., Catrina, A. I., . . . Göransson, U. (2018). Stabilized Cyclic Peptides as Scavengers of Autoantibodies: Neutralization of Anticitrullinated Protein/Peptide Antibodies in Rheumatoid Arthritis. ACS Chemical Biology, 13(6), 1525-1535
Öppna denna publikation i ny flik eller fönster >>Stabilized Cyclic Peptides as Scavengers of Autoantibodies: Neutralization of Anticitrullinated Protein/Peptide Antibodies in Rheumatoid Arthritis
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2018 (Engelska)Ingår i: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 13, nr 6, s. 1525-1535Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The occurrence of autoantibodies is a hallmark of rheumatoid arthritis, specifically those autoantibodies targeting proteins containing the arginine-derived amino acid citrulline. There is strong evidence showing that the occurrence of anticitrullinated protein/peptide antibodies (ACPA) are involved in disease progression, and ACPA was recently shown to induce pain in animals. Here, we explore a novel concept useful for research, diagnostics, and possibly therapy of autoimmune diseases, namely, to directly target and neutralize autoantibodies using peptide binders. A high-affinity peptide-based scavenger of ACPA was developed by grafting a citrullinated epitope derived from human fibrinogen into a naturally occurring stable peptide scaffold. The best scavenger comprises the truncated epitope alpha-fibrinogen, [Cit573]fib(566-580), grafted into the scaffold sunflower trypsin inhibitor-1, SFTI-1. The final peptide demonstrates low nanomolar apparent affinity and superior stability.

Ort, förlag, år, upplaga, sidor
AMER CHEMICAL SOC, 2018
Nationell ämneskategori
Reumatologi och inflammation
Identifikatorer
urn:nbn:se:uu:diva-358527 (URN)10.1021/acschembio.8b00118 (DOI)000435746200015 ()29630823 (PubMedID)
Forskningsfinansiär
Vetenskapsrådet, 2012-5063Vetenskapsrådet, 2017-02577Stiftelsen för strategisk forskning (SSF), F06-0058Reumatikerförbundet, R-755861Stockholms läns landsting, 20160378
Tillgänglig från: 2018-09-03 Skapad: 2018-09-03 Senast uppdaterad: 2018-09-03Bibliografiskt granskad
Hellinger, R., Thell, K., Vasileva, M., Muhammad, T., Gunasekera, S., Kuemmel, D., . . . Gruber, C. W. (2017). Chemical Proteomics for Target Discovery of Head-to-Tail Cyclized Mini-Proteins. Frontiers in Chemistry, 5, Article ID 73.
Öppna denna publikation i ny flik eller fönster >>Chemical Proteomics for Target Discovery of Head-to-Tail Cyclized Mini-Proteins
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2017 (Engelska)Ingår i: Frontiers in Chemistry, E-ISSN 2296-2646, Vol. 5, artikel-id 73Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Target deconvolution is one of the most challenging tasks in drug discovery, but a key step in drug development. In contrast to small molecules, there is a lack of validated and robust methodologies for target elucidation of peptides. In particular, it is difficult to apply these methods to cyclic and cysteine-stabilized peptides since they exhibit reduced amenability to chemical modification and affinity capture; however, such ribosomally synthesized and post-translationally modified peptide natural products are rich sources of promising drug candidates. For example, plant-derived circular peptides called cyclotides have recently attracted much attention due to their immunosuppressive effects and oral activity in the treatment of multiple sclerosis in mice, but their molecular target has hitherto not been reported. In this study, a chemical proteomics approach using photo-affinity crosslinking was developed to determine a target for the circular peptide [T20K]kalata B1. Using this prototypic nature-derived peptide enabled the identification of a possible functional modulation of 14-3-3 proteins. This biochemical interaction was validated via competition pull down assays as well as a cellular reporter assay indicating an effect on 14-3-3-dependent transcriptional activity. As proof of concept, the presented approach may be applicable for target elucidation of various cyclic peptides and mini-proteins, in particular cyclotides, which represent a promising class of molecules in drug discovery and development.

Ort, förlag, år, upplaga, sidor
FRONTIERS MEDIA SA, 2017
Nyckelord
cyclotides, cyclic protein, chemical proteomics, peptide-protein interaction, photo-affinity labeling
Nationell ämneskategori
Farmaceutiska vetenskaper
Identifikatorer
urn:nbn:se:uu:diva-338516 (URN)10.3389/fchem.2017.00073 (DOI)000412726000001 ()29075625 (PubMedID)
Forskningsfinansiär
Australian Research Council, FT140100730
Tillgänglig från: 2018-01-15 Skapad: 2018-01-15 Senast uppdaterad: 2018-01-15Bibliografiskt granskad
Mohotti, S., Rajendran, S., Muhammad, T., Strömstedt, A. A., Burman, R., Hellman, B., . . . Gunasekera, S. (2016). A bioactivity-guided screening of Sri Lankan plants in the search for novel antibacterial and anticancer agents. Paper presented at 9th Joint Meeting of AFERP, ASP, GA, JSP, PSE and SIF, JUL 24-27, 2016, Copenhagen, DENMARK. Planta Medica, 82
Öppna denna publikation i ny flik eller fönster >>A bioactivity-guided screening of Sri Lankan plants in the search for novel antibacterial and anticancer agents
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2016 (Engelska)Ingår i: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 82Artikel i tidskrift, Meeting abstract (Övrigt vetenskapligt) Published
Nyckelord
Ayurvedic, MIC, NMR, FMCA, antibacterial, anticancer
Nationell ämneskategori
Farmakologi och toxikologi
Identifikatorer
urn:nbn:se:uu:diva-346857 (URN)10.1055/s-0036-1596561 (DOI)000411789300385 ()
Konferens
9th Joint Meeting of AFERP, ASP, GA, JSP, PSE and SIF, JUL 24-27, 2016, Copenhagen, DENMARK
Tillgänglig från: 2018-03-27 Skapad: 2018-03-27 Senast uppdaterad: 2018-03-27Bibliografiskt granskad
Gunasekera, S., Fernandes-Cerqueira, C., Eriksson, C., Jakobsson, P.-J. & Göransson, U. (2016). Anti-Citrullinated Peptide Antibody Inhibitors Based On Sunflower Trypsin Inhibitor-1 Scaffold For Potential Anti-Rheumatoid Arthritis Activity. Journal of Peptide Science, 22(S2), S170-S170
Öppna denna publikation i ny flik eller fönster >>Anti-Citrullinated Peptide Antibody Inhibitors Based On Sunflower Trypsin Inhibitor-1 Scaffold For Potential Anti-Rheumatoid Arthritis Activity
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2016 (Engelska)Ingår i: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 22, nr S2, s. S170-S170Artikel i tidskrift, Meeting abstract (Övrigt vetenskapligt) Published
Nationell ämneskategori
Biokemi och molekylärbiologi
Identifikatorer
urn:nbn:se:uu:diva-331382 (URN)10.1002/psc.2950 (DOI)000398216100317 ()
Tillgänglig från: 2017-10-17 Skapad: 2017-10-17 Senast uppdaterad: 2017-10-17Bibliografiskt granskad
Gunasekera, S., Fernandes-Cerqueira, C., Eriksson, C., Jakobsson, P. J. & Göransson, U. (2016). Circular disulfide-rich peptide scaffolds as anti-citrullinated peptide antibody inhibitors. Paper presented at 9th Joint Meeting of AFERP, ASP, GA, JSP, PSE and SIF, JUL 24-27, 2016, Copenhagen, DENMARK. Planta Medica, 82
Öppna denna publikation i ny flik eller fönster >>Circular disulfide-rich peptide scaffolds as anti-citrullinated peptide antibody inhibitors
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2016 (Engelska)Ingår i: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 82Artikel i tidskrift, Meeting abstract (Övrigt vetenskapligt) Published
Nyckelord
anti-citrullinated protein/peptide antibodies (ACPA), cyclic peptide, fibrinogen, NMR, target, sunflower trypsin inhibitor 1 (SFTI-1)
Nationell ämneskategori
Farmakologi och toxikologi
Identifikatorer
urn:nbn:se:uu:diva-346853 (URN)10.1055/s-0036-1596779 (DOI)000411789300603 ()
Konferens
9th Joint Meeting of AFERP, ASP, GA, JSP, PSE and SIF, JUL 24-27, 2016, Copenhagen, DENMARK
Tillgänglig från: 2018-03-27 Skapad: 2018-03-27 Senast uppdaterad: 2018-03-27Bibliografiskt granskad
Muhammad, T., Gunasekera, S., Strömstedt, A. A. & Göransson, U. (2016). Engineering Of A Minimalized Domain Derived From Human Host Defense Peptide LL-37 Into A Stable And Potent Antimicrobial Drug Lead. Journal of Peptide Science, 22(S2), S184-S186
Öppna denna publikation i ny flik eller fönster >>Engineering Of A Minimalized Domain Derived From Human Host Defense Peptide LL-37 Into A Stable And Potent Antimicrobial Drug Lead
2016 (Engelska)Ingår i: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 22, nr S2, s. S184-S186Artikel i tidskrift, Meeting abstract (Övrigt vetenskapligt) Published
Nationell ämneskategori
Biokemi och molekylärbiologi
Identifikatorer
urn:nbn:se:uu:diva-331384 (URN)10.1002/psc.2950 (DOI)000398216100347 ()
Tillgänglig från: 2017-10-17 Skapad: 2017-10-17 Senast uppdaterad: 2017-10-17Bibliografiskt granskad
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