| 1. |
- Bargholtz, Marcus, et al.
(författare)
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Test–Retest Reliability, Agreement and Criterion Validity of Three Questionnaires for the Assessment of Physical Activity and Sedentary Time in Patients with Myocardial Infarction
- 2023
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Ingår i: International Journal of Environmental Research and Public Health. - : MDPI. - 1661-7827 .- 1660-4601. ; 20:16
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Tidskriftsartikel (refereegranskat)abstract
- Regular physical activity (PA) and limited sedentary time (SED) are highly recommended in international guidelines for patients after a myocardial infarction (MI). Data on PA and SED are often self-reported in clinical practice and, hence, reliable and valid questionnaires are crucial. This study aimed to assess the test–retest reliability, criterion validity and agreement of two PA and one SED questionnaire commonly used in clinical practice, developed by the Swedish National Board of Health and Welfare (BHW) and the Swedish national quality register SWEDEHEART. Data from 57 patients (mean age 66 ± 9.2 years, 42 males) was included in this multi-centre study. The patients answered three questionnaires on PA and SED at seven-day intervals and wore an accelerometer for seven days. Test–retest reliability, criterion validity and agreement were assessed using Spearman’s rho and linearly weighted kappa. Test–retest reliability was moderate for three of the six-sub questions (k = 0.43–0.54) within the PA questionnaires. For criterion validity, the correlation was fair within three of the six sub-questions (r = 0.41–0.50) within the PA questionnaires. The SED questionnaire had low agreement (k = 0.12) and criterion validity (r = 0.30). The studied questionnaires for PA could be used in clinical practice as a screening tool and/or to evaluate the level of PA in patients with an MI. Future research is recommended to develop and/or evaluate SED questionnaires in patients with an MI.
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| 2. |
- Björk, Linnea, et al.
(författare)
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Amino-Acid Side-Chain Nanoarchitectonics for Tuning the Chiroptical Properties and Supramolecular Structure of Pentameric Oligothiophenes
- 2024
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Ingår i: ChemPhotoChem. - : WILEY-V C H VERLAG GMBH. - 2367-0932.
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Tidskriftsartikel (refereegranskat)abstract
- Oligothiophenes with specific photophysical properties and molecular organization are of great interest, since this class of materials are used in organic electronics and bioelectronics, as well as biosensing. Herein, 8 different pentameric oligothiophenes, denoted proteophenes, with different amino acid substitution patterns at distinct positions along the thiophene backbone were investigated. Spectroscopic and microscopic studies of the ligands revealed the formation of optically active self-assembled materials under acidic or basic conditions. The distinct photophysical characteristics, including induced circular dichroism, as well as the supramolecular structures of the assemblies deduced from light scattering and transmission electron microscopy, were highly influenced by the positioning of distinct amino acid moieties along the thiophene backbone. Proteophenes functionalized with only glutamate residues or these functionalities in combination with hydrophobic valine moieties formed fibrillar structures with excellent chiroptical properties under acidic conditions. In addition, the amino acid functionality at the beta-position of distinct thiophene moieties influenced the induced circular dichroism pattern observed from the proteophenes. Overall, the obtained results demonstrate how changes in the position of various amino acid functionalities, as well as the chemical nature of the amino acid side chain functionality greatly affect the optical properties as well as the architecture of the self-assembled materials. Self-assembled Proteophenes. Oligothiophenes with distinct amino acid side-chain functionalities along the conjugated backbone displayed distinct chiroptical and structural properties in acidic or alkaline solutions. The distinct photophysical characteristics, as well as the supramolecular structures of the assemblies were highly influenced by the chemical nature of the amino acid, as well as the positioning of distinct amino acid moieties along the thiophene backbone.image
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| 3. |
- 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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| 4. |
- Bäck, Marcus, et al.
(författare)
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Anionic Oligothiophenes Compete for Binding of X-34 but not PIB to Recombinant A beta Amyloid Fibrils and Alzheimers Disease Brain-Derived A beta
- 2016
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Ingår i: CHEMISTRY-A EUROPEAN JOURNAL. - : WILEY-V C H VERLAG GMBH. - 0947-6539. ; 22:51, s. 18335-18338
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Tidskriftsartikel (refereegranskat)abstract
- Deposits comprised of amyloid- (A) are one of the pathological hallmarks of Alzheimers disease (AD) and small hydrophobic ligands targeting these aggregated species are used clinically for the diagnosis of AD. Herein, we observed that anionic oligothiophenes efficiently displaced X-34, a Congo Red analogue, but not Pittsburgh compoundB (PIB) from recombinant A amyloid fibrils and Alzheimers disease brain-derived A. Overall, we foresee that the oligothiophene scaffold offers the possibility to develop novel high-affinity ligands for A pathology only found in human AD brain, targeting a different site than PIB.
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| 5. |
- 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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| 6. |
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| 7. |
- 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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| 8. |
- Bäck, Marcus, et al.
(författare)
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Design, synthesis and SAR of potent statine-based BACE-1 inhibitors : Exploration of P1 phenoxy and benzyloxy residues
- 2008
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 16:21, s. 9471-9486
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Tidskriftsartikel (refereegranskat)abstract
- Several BACE-1 inhibitors with low nanomolar level activities, encompassing a statine-based core structure with phenyloxymethyl- and benzyloxymethyl residues in the P1 position, are presented. The novel P1 modi. cation introduced to allow the facile exploration of the S1 binding pocket of BACE-1, delivered highly promising inhibitors.
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| 9. |
- Bäck, Marcus, et al.
(författare)
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Novel potent macrocyclic inhibitors of the hepatitis C virus NS3 protease : use of cyclopentane and cyclopentene P2-motifs
- 2007
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 15:22, s. 7184-7202
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Tidskriftsartikel (refereegranskat)abstract
- Several highly potent novel HCV NS3 protease inhibitors have been developed from two inhibitor series containing either a P2 trisubstituted macrocyclic cyclopentane- or a P2 cyclopentene dicarboxylic acid moiety as surrogates for the widely used N-acyl-(4R)-hydroxyproline in the P2 position. These inhibitors were optimized for anti HCV activities through examination of different ring sizes in the macrocyclic systems and further by exploring the effect of P4 substituent removal on potency. The target molecules were synthesized from readily available starting materials, furnishing the inhibitor compounds in good overall yields. It was found that the 14-membered ring system was the most potent in these two series and that the corresponding 13-, 15-, and 16-membered macrocyclic rings delivered less potent inhibitors. Moreover, the corresponding P1 acylsulfonamides had superior potencies over the corresponding P1 carboxylic acids. It is noteworthy that it has been possible to develop highly potent HCV protease inhibitors that altogether lack the P4 substituent. Thus the most potent inhibitor described in this work, inhibitor 20, displays a Ki value of 0.41 nM and an EC50 value of 9 nM in the subgenomic HCV replicon cell model on genotype 1b. To the best of our knowledge this is the first example described in the literature of a HCV protease inhibitor displaying high potency in the replicon assay and lacking the P4 substituent, a finding which should facilitate the development of orally active small molecule inhibitors against the HCV protease.
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| 10. |
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