| 1. |
- Björk, Linnea, et al.
(författare)
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Proteophenes - Amino Acid Functionalized Thiophene-based Fluorescent Ligands for Visualization of Protein Deposits in Tissue Sections with Alzheimers Disease Pathology
- 2022
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Ingår i: Chemistry - A European Journal. - : Wiley-V C H Verlag GMBH. - 0947-6539 .- 1521-3765. ; 28:62
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Tidskriftsartikel (refereegranskat)abstract
- Protein deposits composed of specific proteins or peptides are associated with several neurodegenerative diseases and fluorescent ligands able to detect these pathological hallmarks are vital. Here, we report the synthesis of a class of thiophene-based ligands, denoted proteophenes, with different amino acid side-chain functionalities along the conjugated backbone, which display selectivity towards specific disease-associated protein aggregates in tissue sections with Alzheimers disease (AD) pathology. The selectivity of the ligands towards AD associated pathological hallmarks, such as aggregates of the amyloid-beta (A beta) peptide or tau filamentous inclusions, was highly dependent on the chemical nature of the amino acid functionality, as well as on the location of the functionality along the pentameric thiophene backbone. Finally, the concept of synthesizing donor-acceptor-donor proteophenes with distinct photophysical properties was shown. Our findings provide the structural and functional basis for the development of new thiophene-based ligands that can be utilized for optical assignment of different aggregated proteinaceous species in tissue sections.
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| 2. |
- Bäck, Marcus, 1979-
(författare)
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Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors Incorporating a P2 Cyclopentane-Derived Scaffold
- 2006
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis describes the design, synthesis and structure-activity relationships analysis of potential inhibitors targeting the hepatitis C virus (HCV) NS3 protease. Also discussed is the disease caused by HCV infection and the class of enzymes known as proteases. Furthermore are explained why such enzymes can be considered to be suitable targets for developing drugs to combat diseases in general and in particular HCV, focusing on the NS3 protease. Moreover, some strategies used to design protease inhibitors and the desired properties of potential drug candidates are briefly examined. Synthesis of linear and macrocyclic NS3 protease inhibitors comprising a designed trisubstituted cyclopentane moiety as an N-acyl-(4R)-hydroxyproline bioisostere is also addressed, and several very potent and promising compounds are evaluated.
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| 3. |
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| 4. |
- Bäck, Marcus, 1979-
(författare)
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Design and Synthesis of Inhibitors Targeting the Hepatitis C Virus NS3 Serine Protease and the Aspartic Protease BACE-1
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis describes the synthesis of molecules designed to inhibit the hepatitis C virus (HCV) NS3 serine protease and the human aspartic protease BACE-1, and it also reports the structure-activity relationships between potential inhibitors and the targeted enzymes. In addition, consideration is given to the class of enzymes known as proteases, as well as the question of why such enzymes can be regarded as suitable targets for developing drugs to combat diseases in general. Some strategies used to design protease inhibitors and the desired properties of such potential drug candidates are also briefly examined.Infection with HCV gives rise to a predominantly chronic disease that causes severe liver damage and ultimately leads to cirrhosis and liver cancer, and hence it represents the main factor underlying most of the liver transplants in the developed world. The HCV NS3 serine protease is essential for replication of the virus, and it has become one of the most widely exploited targets for developing anti-HCV inhibitors. The results presented here concern the design and synthesis of linear and macrocyclic NS3 protease inhibitors containing a novel trisubstituted cyclopentane moiety as an N-acyl-(4R)-hydroxyproline bioisostere. Several highly potent compounds were evaluated, including inhibitors with Ki and replicon EC50 values in the subnanomolar and the low nanomolar range, respectively.Alzheimer’s disease is a fatal neurodegenerative disorder of the brain. It is characterized by loss of memory and cognition, and is associated with accumulation of plaques and tangles that cause serious impairment and functional decline of brain tissues. The plaques consist mainly of amyloid-β fragments that are generated through two cleavages of amyloid precursor protein (APP). The enzyme responsible for the initial cleavage is the aspartic protease BACE-1 (beta-site APP-cleaving enzyme), which was explored in the current studies as a pharmaceutical target. The synthetic work comprised development of two series of BACE-1 inhibitors with different central core isosteres; a statine-based and a hydroxyethylene-based series. Highly potent inhibitors were produced by varying the substituents coupled to the statine-based central core. X-ray crystallography and molecular modeling enabled analysis of the binding properties of these compounds. In the second series a hydroxyethylene central core was decorated with more advanced P1 substituents with the aim of increasing the binding interactions with the S1 site. This resulted in inhibitors with more drug-like properties and activities in the low micromolar range.
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| 5. |
- Choong, FX, et al.
(författare)
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Real-time optotracing of curli and cellulose in live Salmonella biofilms using luminescent oligothiophenes
- 2016
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Ingår i: NPJ biofilms and microbiomes. - : Springer Science and Business Media LLC. - 2055-5008. ; 2, s. 16024-
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Tidskriftsartikel (refereegranskat)abstract
- Extracellular matrix (ECM) is the protein- and polysaccharide-rich backbone of bacterial biofilms that provides a defensive barrier in clinical, environmental and industrial settings. Understanding the dynamics of biofilm formation in native environments has been hindered by a lack of research tools. Here we report a method for simultaneous, real-time, in situ detection and differentiation of the Salmonella ECM components curli and cellulose, using non-toxic, luminescent conjugated oligothiophenes (LCOs). These flexible conjugated polymers emit a conformation-dependent fluorescence spectrum, which we use to kinetically define extracellular appearance of curli fibres and cellulose polysaccharides during bacterial growth. The scope of this technique is demonstrated by defining biofilm morphotypes of Salmonella enterica serovars Enteritidis and Typhimurium, and their isogenic mutants in liquid culture and on solid media, and by visualising the ECM components in native biofilms. Our reported use of LCOs across a number of platforms, including intracellular cellulose production in eukaryotic cells and in infected tissues, demonstrates the versatility of this optotracing technology, and its ability to redefine biofilm research.
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| 6. |
- Rouhbakhsh, Zeinab, et al.
(författare)
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Self-Assembly of a Structurally Defined Chiro-Optical Peptide-Oligothiophene Hybrid Material
- 2018
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Ingår i: ACS Omega. - : American Chemical Society (ACS). - 2470-1343. ; 3:11, s. 15066-15075
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Tidskriftsartikel (refereegranskat)abstract
- Conducting polymers are routinely used in optoelectronic biomaterials, but large polymer polydispersity and poor aqueous compatibility complicate integration with biomolecular templates and development of discrete and defined supramolecular complexes. Herein, we report on a chiro-optical hybrid material generated by the self-assembly of an anionic peptide and a chemically defined cationic pentameric thiophene in aqueous environment. The peptide acts as a stereochemical template for the thiophene and adopts an α-helical conformation upon association, inducing optical activity in the thiophene π-π* transition region. Theoretical calculations confirm the experimentally observed induced structural changes and indicate the importance of electrostatic interactions in the complex. The association process is also probed at the substrate-solvent interface using peptide-functionalized gold nanoparticles, indicating that the peptide can also act as a scaffold when immobilized, resulting in structurally well-defined supramolecular complexes. The hybrid complex could rapidly be assembled, and the kinetics of the formation could be monitored by utilizing the local surface plasmon resonance originating from the gold nanoparticles. We foresee that these findings will aid in designing novel hybrid materials and provide a possible route for the development of functional optoelectronic interfaces for both biomaterials and energy harvesting applications.
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| 7. |
- Snipstad, Sofie, et al.
(författare)
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Labeling nanoparticles : Dye leakage and altered cellular uptake
- 2017
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Ingår i: Cytometry Part A. - : John Wiley & Sons. - 1552-4922 .- 1552-4930. ; 91:8, s. 760-766
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Tidskriftsartikel (refereegranskat)abstract
- In vitro and in vivo behavior of nanoparticles (NPs) is often studied by tracing the NPs with fluorescent dyes. This requires stable incorporation of dyes within the NPs, as dye leakage may give a wrong interpretation of NP biodistribution, cellular uptake, and intracellular distribution. Furthermore, NP labeling with trace amounts of dye should not alter NP properties such as interactions with cells or tissues. To allow for versatile NP studies with a variety of fluorescence-based assays, labeling of NPs with different dyes is desirable. Hence, when new dyes are introduced, simple and fast screening methods to assess labeling stability and NP-cell interactions are needed. For this purpose, we have used a previously described generic flow cytometry assay; incubation of cells with NPs at 4 and 37C. Cell-NP interaction is confirmed by cellular fluorescence after 37C incubation, and NP-dye retention is confirmed when no cellular fluorescence is detected at 4C. Three different NP-platforms labeled with six different dyes were screened, and a great variability in dye retention was observed. Surprisingly, incorporation of trace amounts of certain dyes was found to reduce or even inhibit NP uptake. This work highlights the importance of thoroughly evaluating every dye-NP combination before pursuing NP-based applications. © 2016 International Society for Advancement of Cytometry.
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