| 1. |
- Abdurahman, Samir, et al.
(författare)
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Anti-HIV activity of the small modified amino acid {alpha}-hydroxy glycineamide on in vitro and in vivo HIV-1 capsid assembly and infectivity
- 2008
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Ingår i: Antimicrobial Agents and Chemotherapy. - 1098-6596. ; 52:10, s. 3737-3744
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Tidskriftsartikel (refereegranskat)abstract
- Upon maturation of the HIV-1 virion, proteolytic cleavage of the Gag precursor protein by the viral protease is followed by morphological changes of the capsid protein p24 which will ultimately transform the virus core from an immature spherical to a mature conical structure. Virion infectivity is critically dependent on the just right semi-stability of the capsid cone structure. We have earlier reported that glycineamide (G-NH2) when added to the culture medium of infected cells inhibits HIV-1 replication and that HIV-1 particles with aberrant core structures were formed. Here we show that it is not G-NH2 itself but a metabolite thereof, alpha-hydroxy-glycineamide (alpha-HGA), that is responsible for the antiviral activity. We show that alpha-HGA inhibits the replication of clinical HIV-1 isolates with acquired resistance to reverse transcriptase and protease inhibitors but has no effect on the replication of any of ten different RNA and DNA viruses. alpha-HGA affected the ability of the HIV-1 capsid protein to assemble into tubular or core structures in vitro and in vivo, probably by binding to the hinge region between the N- and C-terminal domains of the HIV-1 capsid protein as indicated by MALDI-MS results. As an antiviral compound, alpha-HGA has an unusually simple structure, a pronounced antiviral specificity and a novel mechanism of antiviral action. As such, it might prove to be a lead compound for a new class of anti-HIV substances.
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| 2. |
- Abdurahman, Samir, 1965-, et al.
(författare)
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Isolation and characterization of a small antiretroviral molecule affecting HIV-1 capsid morphology
- 2009
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Ingår i: Retrovirology. - : Springer Science and Business Media LLC. - 1742-4690. ; 6, s. 34-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Formation of an HIV-1 particle with a conical core structure is a prerequisite for the subsequent infectivity of the virus particle. We have previously described that glycineamide (G-NH2) when added to the culture medium of infected cells induces non-infectious HIV-1 particles with aberrant core structures. Results: Here we demonstrate that it is not G-NH2 itself but a metabolite thereof that displays antiviral activity. We show that conversion of G-NH2 to its antiviral metabolite is catalyzed by an enzyme present in bovine and porcine but surprisingly not in human serum. Structure determination by NMR suggested that the active G-NH2 metabolite was alpha-hydroxy-glycineamide (alpha-HGA). Chemically synthesized alpha-HGA inhibited HIV-1 replication to the same degree as G-NH2, unlike a number of other synthesized analogues of G-NH2 which had no effect on HIV-1 replication. Comparisons by capillary electrophoresis and HPLC of the metabolite with the chemically synthesized alpha-HGA further confirmed that the antiviral G-NH2-metabolite indeed was alpha-HGA. Conclusion: alpha-HGA has an unusually simple structure and a novel mechanism of antiviral action. Thus, alpha-HGA could be a lead for new antiviral substances belonging to a new class of anti-HIV drugs, i.e. capsid assembly inhibitors.
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| 3. |
- Anderot, Maria, et al.
(författare)
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Determination of dissociation constants between polyelectrolytes and proteins by affinity capillary electrophoresis
- 2009
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Ingår i: Journal of chromatography. B. - : Elsevier BV. - 1570-0232 .- 1873-376X. ; 877:10, s. 892-896
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Tidskriftsartikel (refereegranskat)abstract
- In this manuscript we report the binding affinity between two model proteins, human serum albumin (HSA) and ribonuclease A (RNase A), and negatively charged polyelectrolytes, two different heparin fractions and dextran sulfate, by means of partial filling and affinity capillary electrophoresis. The apparent dissociation constants, K-d, obtained by use of the partial-filling method, between HSA and heparin (17 kDa), heparin (3 kDa) and dextran sulfate (8 kDa) were 33 and 307 mu M, respectively. A new method was developed to determine affinities that take in account different migration directions between the protein and the polyelectrolyte, which was required to study RNase A. By use of this affinity capillary electrophoresis two K-d values were observed for the interaction between RNase A and heparin 17 kDa, yielding a high affinity binding with K-d1 0.0075 mu M, and a lower affinity binding with K-d2 8.7 mu M. For dextran sulfate 8 kDa these K-d values were 0.027 and 10.4 mu M, respectively. Heparin 3 kDa only showed a single K-d value of 0.52 mu M. The results show that the magnitude of the binding affinity depends on the type of polyelectrolyte and its molecular weight. (C) 2009 Elsevier B.V. All rights reserved.
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| 4. |
- Fehniger, Thomas, et al.
(författare)
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International Biobanking for Lung Cancer and COPD as the Future Resource for Clinical Protein Research
- 2013
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Ingår i: EuPA Open Proteomics. - : Elsevier BV. - 2212-9685. ; 1, s. 3-7
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Tidskriftsartikel (refereegranskat)abstract
- Characterized tissue with pathological grading and blood samples as well as other biofluids forms the basis for all biobanks as a resource in modern life science. Biobanks are accessed to measure biological components that can be used to monitor the status of health and disease in individual samples and population groups. The biomarker diagnostics area, predicting drug efficacy, stratification of patient groups, can benefit from the continuous qualitative developments, where Proteomics can make a difference in lung cancer and COPD. This in turn can provide key treasures to novel drugs for personalized medicine in the future.
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| 5. |
- Fehniger, Thomas, et al.
(författare)
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Queries of MALDI-Imaging Global Datasets Identifying Ion Mass Signatures Associated with Tissue Compartments
- 2014
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Ingår i: Proteomics. - : Wiley. - 1615-9861 .- 1615-9853. ; 14:7-8, s. 862-871
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Tidskriftsartikel (refereegranskat)abstract
- Scanning mass spectrometry by matrix assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) creates large volumetric global datasets that describe the location and identity of ions registered at each sampling location. While thousands of ion peaks are recorded in a typical whole tissue analysis, only a fraction of these measured molecules are purposefully scrutinized within a given experimental design. To address this need, we recently reported new methods to query the full volume of MALDI-MSI data that correlate all ion masses to one another. As an example of this utility we demonstrate that specific ion peak m/z signatures can be used to localize similar histological structures within tissue samples. In this study we use the example of ion peak masses that are associated with tissue spaces occupied by airway bronchioles in rat lung samples. The volume of raw data was pre-processed into structures of 0.1 mass unit bins containing metadata collected at each sampling position. Interactive visualization in Paraview identified ion peaks that especially showed strong association with airway bronchioles but not vascular or parenchymal tissue compartments. Further iterative statistical correlation queries provided ranked indices of all m/z values in the global dataset regarding co-incident distributions at any given X,Y position in the histological spaces occupied by bronchioles The study further provides methods for extracting important information contained in global datasets that previously was unseen or inaccessible. This article is protected by copyright. All rights reserved.
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| 6. |
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| 7. |
- Gonzalez, Henrik, et al.
(författare)
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Identification of novel candidate protein biomarkers for the post-polio syndrome — Implications for diagnosis, neurodegeneration and neuroinflammation
- 2009
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Ingår i: Journal of Proteomics. - : Elsevier BV. - 1874-3919 .- 1876-7737. ; 71:6, s. 670-681
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Tidskriftsartikel (refereegranskat)abstract
- Survivors of poliomyelitis often develop increased or new symptoms decades after the acute infection, a condition known as post-polio syndrome (PPS). The condition affects 20-60% of previous polio patients, making it one of the most common causes of neurological deficits worldwide. The underlying pathogenesis is not fully understood and accurate diagnosis is not feasible. Herein we investigated whether it was possible to identify proteomic profile aberrations in the cerebrospinal fluid (CSF) of PPS patients. CSF from 15 patients with well-defined PPS were analyzed for protein expression profiles. The results were compared to data obtained from nine healthy controls and 34 patients with other non-inflammatory diseases which served as negative controls. In addition, 17 samples from persons with secondary progressive multiple sclerosis (SPMS) were added as relevant age-matched references for the PPS samples. The CSF of persons with PPS displayed a disease-specific and highly predictive (p=0.0017) differential expression of five distinct proteins: gelsolin, hemopexin, peptidylglycine alpha-amidating monooxygenase, glutathione synthetase and kallikrein 6, respectively, in comparison with the control groups. An independent ELISA confirmed the increase of kallikrein 6. We suggest that these five proteins should be further evaluated as candidate biomarkers for the diagnosis and development of new therapies for PPS patients.
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| 8. |
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| 9. |
- Lichti, Cheryl F., et al.
(författare)
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Integrated Chromosome 19 Transcriptomic and Proteomic Data Sets Derived from Glioma Cancer Stem-Cell Lines
- 2014
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Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 13:1, s. 191-199
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Tidskriftsartikel (refereegranskat)abstract
- One subproject within the global Chromosome 19 Consortium is to define chromosome 19 gene and protein expression in glioma-derived cancer stem cells (GSCs). Chromosome 19 is notoriously linked to glioma by 1p/19q codeletions, and clinical tests are established to detect that specific aberration. GSCs are tumor-initiating cells and are hypothesized to provide a repository of cells in tumors that can self-replicate and be refractory to radiation and chemotherapeutic agents developed for the treatment of tumors. In this pilot study, we performed RNA-Seq, label-free quantitative protein measurements in six GSC lines, and targeted transcriptomic analysis using a chromosome 19-specific microarray in an additional six GSC lines. The data have been deposited to the ProteomeXchange with identifier PXD000563. Here we present insights into differences in GSC gene and protein expression, including the identification of proteins listed as having no or low evidence at the protein level in the Human Protein Atlas, as correlated to chromosome 19 and GSC subtype. Furthermore, the upregulation of proteins downstream of adenovirus-associated integration site 1 (AAVS1) in GSC11 in response to oncolytic adenovirus treatment was demonstrated. Taken together, our results may indicate new roles for chromosome 19, beyond the 1p/19q codeletion, in the future of personalized medicine for glioma patients.
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| 10. |
- Lichti, Cheryl, et al.
(författare)
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Systematic Identification of Single Amino Acid Variants in Glioma Stem-Cell-Derived Chromosome 19 Proteins
- 2015
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Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 14:2, s. 778-786
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Tidskriftsartikel (refereegranskat)abstract
- Novel proteoforms with single amino acid polymorphism represent proteins that often have altered biological functions but are less explored in the human proteome. We have developed an approach, searching high quality shotgun proteomic data against an extended protein database, to identify expressed mutant proteoforms in glioma stem cell (GSC) lines. The systematic search of MS/MS spectra has recognized 13 chromosome 19 proteins in GSCs with altered amino acid sequences using PEAKS 7.0 as the search engine. The results were further verified by manual spectral examination, validating 14 proteoforms. One of the novel findings, a mutant form of branched-chain aminoacyl transferase 2 (T186R), was verified at the transcript level and by SRM in several glioma stem cell lines. The structure of this proteoform examined by molecular modeling to estimate structural changes of mutation that could lead to functional modifications potentially linked to glioma. Based on our initial findings, we believe that our approach presented could contribute to construct a more complete map of the human functional proteome.
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