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Jayaweera, Sanduni Wasana
Publications (5 of 5) Show all publications
Gharibyan, A., Jayaweera, S. W., Lehmann, M., Anan, I. & Olofsson, A. (2022). Endogenous Human Proteins Interfering with Amyloid Formation. Biomolecules, 12(3), Article ID 446.
Open this publication in new window or tab >>Endogenous Human Proteins Interfering with Amyloid Formation
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2022 (English)In: Biomolecules, E-ISSN 2218-273X, Vol. 12, no 3, article id 446Article, review/survey (Refereed) Published
Abstract [en]

Amyloid formation is a pathological process associated with a wide range of degenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and diabetes mellitus type 2. During disease progression, abnormal accumulation and deposition of proteinaceous material are accompanied by tissue degradation, inflammation, and dysfunction. Agents that can interfere with the process of amyloid formation or target already formed amyloid assemblies are consequently of therapeutic interest. In this context, a few endogenous proteins have been associated with an anti-amyloidogenic activity. Here, we review the properties of transthyretin, apolipoprotein E, clusterin, and BRICHOS protein domain which all effectively interfere with amyloid in vitro, as well as displaying a clinical impact in humans or animal models. Their involvement in the amyloid formation process is discussed, which may aid and inspire new strategies for therapeutic interventions.

Place, publisher, year, edition, pages
MDPI, 2022
Keywords
Alpha-synuclein, Amyloid inhibition, Amyloid-beta, Apolipoprotein E, BRICHOS, Clusterin, Endogenous proteins, IAPP, Transthyretin
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-193407 (URN)10.3390/biom12030446 (DOI)000775848600001 ()2-s2.0-85126704016 (Scopus ID)
Available from: 2022-03-31 Created: 2022-03-31 Last updated: 2023-09-05Bibliographically approved
Bharate, J. B., Ådén, J., Gharibyan, A., Adolfsson, D. E., Jayaweera, S. W., Singh, P., . . . Almqvist, F. (2021). K2S2O8-mediated coupling of 6-amino-7-aminomethyl-thiazolino-pyridones with aldehydes to construct amyloid affecting pyrimidine-fused thiazolino-2-pyridones. Organic and biomolecular chemistry, 19(44), 9758-9772
Open this publication in new window or tab >>K2S2O8-mediated coupling of 6-amino-7-aminomethyl-thiazolino-pyridones with aldehydes to construct amyloid affecting pyrimidine-fused thiazolino-2-pyridones
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2021 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 19, no 44, p. 9758-9772Article in journal (Refereed) Published
Abstract [en]

We herein present the synthesis of diversely functionalized pyrimidine fused thiazolino-2-pyridones via K2S2O8-mediated oxidative coupling of 6-amino-7-(aminomethyl)-thiazolino-2-pyridones with aldehydes. The developed protocol is mild, has wide substrate scope, and does not require transition metal catalyst or base. Some of the synthesized compounds have an ability to inhibit the formation of Amyloid-β fibrils associated with Alzheimer's disease, while others bind to mature amyloid-β and α-synuclein fibrils.

Place, publisher, year, edition, pages
The Royal Society of Chemistry, 2021
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-189516 (URN)10.1039/D1OB01580J (DOI)000714122800001 ()34730163 (PubMedID)2-s2.0-85120001225 (Scopus ID)
Funder
Swedish Research Council, 2017-02339; 2017-00695; 2018-04589Knut and Alice Wallenberg Foundation, 2013.0031Göran Gustafsson Foundation for Research in Natural Sciences and MedicineSwedish Foundation for Strategic Research, SB12-0070NIH (National Institutes of Health), (R01AI134847-01A1
Available from: 2021-11-15 Created: 2021-11-15 Last updated: 2023-08-09Bibliographically approved
Jayaweera, S. W., Surano, S., Pettersson, N., Oskarsson, E., Lettius, L., Gharibyan, A. L., . . . Olofsson, A. (2021). Mechanisms of Transthyretin Inhibition of IAPP Amyloid Formation. Biomolecules, 11(3), Article ID 411.
Open this publication in new window or tab >>Mechanisms of Transthyretin Inhibition of IAPP Amyloid Formation
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2021 (English)In: Biomolecules, E-ISSN 2218-273X, Vol. 11, no 3, article id 411Article in journal, Editorial material (Refereed) Published
Abstract [en]

Amyloid-formation by the islet amyloid polypeptide (IAPP), produced by the β-cells in the human pancreas, has been associated with the development of type II diabetes mellitus (T2DM). The human plasma-protein transthyretin (TTR), a well-known amyloid-inhibiting protein, is interestingly also expressed within the IAPP producing β-cells. In the present study, we have characterized the ability of TTR to interfere with IAPP amyloid-formation, both in terms of its intrinsic stability as well as with regard to the effect of TTR-stabilizing drugs. The results show that TTR can prolong the lag-phase as well as impair elongation in the course of IAPP-amyloid formation. We also show that the interfering ability correlates inversely with the thermodynamic stability of TTR, while no such correlation was observed as a function of kinetic stability. Furthermore, we demonstrate that the ability of TTR to interfere is maintained also at the low pH environment within the IAPP-containing granules of the pancreatic β-cells. However, at both neutral and low pH, the addition of TTR-stabilizing drugs partly impaired its efficacy. Taken together, these results expose mechanisms of TTR-mediated inhibition of IAPP amyloid-formation and highlights a potential therapeutic target to prevent the onset of T2DM.

Place, publisher, year, edition, pages
MDPI, 2021
Keywords
IAPP, TTR, amylin, amyloid, diabetes, islet amyloid polypeptide, thioflavin T, transthyretin
National Category
Basic Medicine
Identifiers
urn:nbn:se:umu:diva-182798 (URN)10.3390/biom11030411 (DOI)000633423800001 ()33802170 (PubMedID)2-s2.0-85103862637 (Scopus ID)
Funder
The Swedish Brain Foundation, FO2018-0334Stiftelsen Olle Engkvist Byggmästare, 199-0469Stiftelsen Gamla Tjänarinnor, 2018-00718
Available from: 2021-05-05 Created: 2021-05-05 Last updated: 2023-09-05Bibliographically approved
Tyagi, M., Adolfsson, D. E., Singh, P., Ådén, J., Jayaweera, S. W., Gharibyan, A., . . . Almqvist, F. (2021). Tandem Ring Opening/Intramolecular [2 + 2] Cycloaddition Reaction for the Synthesis of Cyclobutane Fused Thiazolino-2-Pyridones. Journal of Organic Chemistry, 86(23), 16582-16592
Open this publication in new window or tab >>Tandem Ring Opening/Intramolecular [2 + 2] Cycloaddition Reaction for the Synthesis of Cyclobutane Fused Thiazolino-2-Pyridones
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2021 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 86, no 23, p. 16582-16592Article in journal (Refereed) Published
Abstract [en]

Reaction of thiazoline fused 2-pyridones with alkyl halides in the presence of cesium carbonate opens the thiazoline ring via S-alkylation and generates N-alkenyl functionalized 2-pyridones. In the reaction with propargyl bromide, the thiazoline ring opens and subsequently closes via a [2 + 2] cycloaddition between an in situ generated allene and the α,β-unsaturated methyl ester. This method enabled the synthesis of a variety of cyclobutane fused thiazolino-2-pyridones, of which a few analogues inhibit amyloid β1–40 fibril formation. Furthermore, other analogues were able to bind mature α-synuclein and amyloid β1−40 fibrils. Several thiazoline fused 2-pyridones with biological activity tolerate this transformation, which in addition provides an exocyclic alkene as a potential handle for tuning bioactivity.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2021
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-189656 (URN)10.1021/acs.joc.1c01875 (DOI)000752848600030 ()34767366 (PubMedID)2-s2.0-85119436020 (Scopus ID)
Funder
Swedish Research Council, 2017-02339Swedish Research Council, 2017-00695Swedish Research Council, 2018-04589Knut and Alice Wallenberg Foundation, 2013.0031Göran Gustafsson Foundation for Research in Natural Sciences and MedicineThe Kempe Foundations, SMK-1755Swedish Foundation for Strategic Research , SB12-0070NIH (National Institute of Health), (R01AI134847-01A1Familjen Erling-Perssons Stiftelse
Available from: 2021-11-18 Created: 2021-11-18 Last updated: 2023-09-05Bibliographically approved
Adolfsson, D. E., Tyagi, M., Singh, P., Deuschmann, A., Ådén, J., Gharibyan, A., . . . Almqvist, F. (2020). Intramolecular Povarov Reactions for the Synthesis of Chromenopyridine fused 2-Pyridone Polyheterocycles Binding to α-Synuclein and Amyloid-β fibrils. Journal of Organic Chemistry, 85(21), 14174-14189
Open this publication in new window or tab >>Intramolecular Povarov Reactions for the Synthesis of Chromenopyridine fused 2-Pyridone Polyheterocycles Binding to α-Synuclein and Amyloid-β fibrils
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2020 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 85, no 21, p. 14174-14189Article in journal (Other academic) Published
Abstract [en]

A BF3×OEt2 catalyzed intramolecular Povarov reaction was used to synthesize a library of 15 chromenopyridine fused thiazolino-2-pyridone peptidomimetics. The reaction works with a range of O-alkylated salicylaldehydes and amino functionalized thiazolino-2-pyridones, to generate polyheterocycles with diverse substitution. The synthesized compounds were screened for their ability to bind α-synuclein and amyloid β fibrils in vitro. Analogs substituted with a nitro group bind to mature amyloid fibrils, and the activity moreover depends on the positioning of this functional group.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2020
Keywords
Nanofibers, Column chromatography, Peptides and proteins, Mixtures, Alkyls
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-174531 (URN)10.1021/acs.joc.0c01699 (DOI)000589941700068 ()2-s2.0-85095859796 (Scopus ID)
Funder
Swedish Research Council, 2017-02339Swedish Research Council, 2017-00695Swedish Research Council, 2018-04589Knut and Alice Wallenberg Foundation, KAW 2013.0031Göran Gustafsson Foundation for Research in Natural Sciences and MedicineThe Kempe Foundations, SMK-1755Swedish Foundation for Strategic Research , SB12-0070NIH (National Institute of Health), R01AI134847-01A1
Note

Previously included in thesis in manuscript form.

Available from: 2020-08-26 Created: 2020-08-26 Last updated: 2023-03-24Bibliographically approved
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