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- Treusch, Sebastian, et al.
(författare)
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Functional links between Aβ toxicity, endocytic trafficking, and Alzheimer's disease risk factors in yeast
- 2011
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Ingår i: Science. - Washington : American association of advancement in science. - 0036-8075 .- 1095-9203. ; 334:6060, s. 1241-1245
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Tidskriftsartikel (refereegranskat)abstract
- Aβ (beta amyloid peptide) is an important contributor to Alzheimer's disease (AD). We modeled Aβ toxicity in yeast by directing the peptide to the secretory pathway. A genome-wide screen for toxicity modifiers identified the yeast homolog of phosphatidylinositol binding clathrin assembly protein (PICALM) and other endocytic factors connected to AD whose relationship to Aβ was previously unknown. The factors identified in yeast modified Aβ toxicity in glutamatergic neurons of Caenorhabditis elegans and in primary rat cortical neurons. In yeast, Aβ impaired the endocytic trafficking of a plasma membrane receptor, which was ameliorated by endocytic pathway factors identified in the yeast screen. Thus, links between Aβ, endocytosis, and human AD risk factors can be ascertained using yeast as a model system.
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- Brännström, Kristoffer, et al.
(författare)
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A Generic Method for Design of Oligomer-Specific Antibodies
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:3, s. e90857-
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Tidskriftsartikel (refereegranskat)abstract
- Antibodies that preferentially and specifically target pathological oligomeric protein and peptide assemblies, as opposed to their monomeric and amyloid counterparts, provide therapeutic and diagnostic opportunities for protein misfolding diseases. Unfortunately, the molecular properties associated with oligomer-specific antibodies are not well understood, and this limits targeted design and development. We present here a generic method that enables the design and optimisation of oligomer-specific antibodies. The method takes a two-step approach where discrimination between oligomers and fibrils is first accomplished through identification of cryptic epitopes exclusively buried within the structure of the fibrillar form. The second step discriminates between monomers and oligomers based on differences in avidity. We show here that a simple divalent mode of interaction, as within e. g. the IgG isotype, can increase the binding strength of the antibody up to 1500 times compared to its monovalent counterpart. We expose how the ability to bind oligomers is affected by the monovalent affinity and the turnover rate of the binding and, importantly, also how oligomer specificity is only valid within a specific concentration range. We provide an example of the method by creating and characterising a spectrum of different monoclonal antibodies against both the A beta peptide and alpha-synuclein that are associated with Alzheimer's and Parkinson's diseases, respectively. The approach is however generic, does not require identification of oligomer-specific architectures, and is, in essence, applicable to all polypeptides that form oligomeric and fibrillar assemblies.
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- Jivegård, Lennart, 1950, et al.
(författare)
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Effects of three months of low molecular weight heparin (dalteparin) treatment after bypass surgery for lower limb ischemia--a randomised placebo-controlled double blind multicentre trial.
- 2005
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Ingår i: European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery. - : Elsevier BV. - 1078-5884. ; 29:2, s. 190-8
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To test the hypothesis that long-term postoperative dalteparin (Fragmin), Pharmacia Corp) treatment improves primary patency of peripheral arterial bypass grafts (PABG) in lower limb ischemia patients on acetylsalicylic acid (ASA) treatment. DESIGN: Prospective randomised double blind multicenter study. MATERIALS AND METHODS: Using a computer algorithm 284 patients with lower limb ischemia, most with pre-operative ischemic ulceration or partial gangrene, from 12 hospitals were randomised, after PABG, to 5000 IU dalteparin or placebo injections once daily for 3 months. All patients received 75 mg of ASA daily for 12 months. Graft patency was assessed at 1, 3 and 12 months. RESULTS: At 1 year, 42 patients had died or were lost to follow-up. Compliance with the injection schedule was 80%. Primary patency rate, in the dalteparin versus the control group, respectively, was 83 versus 80% (n.s.) at 3 months and 59% for both groups at 12 months. Major complication rates and cardiovascular morbidity were not different between the two groups. CONCLUSIONS: In patients on ASA treatment, long-term postoperative dalteparin treatment did not improve patency after peripheral artery bypass grafting. Therefore, low molecular weight heparin treatment cannot be recommended for routine use after bypass surgery for critical lower limb ischemia.
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- Lindhagen, Elin, et al.
(författare)
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R-etodolac (SDX-101) and the related indole-pyran analogues SDX-308 and SDX-309 potentiate the antileukemic activity of standard cytotoxic agents in primary chronic lymphocytic leukaemia cells
- 2007
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Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 60:4, s. 545-553
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Tidskriftsartikel (refereegranskat)abstract
- Objective: SDX-101 is the non-cyclooxygenase 2-inhibiting R-enantiomer of the non-steroid anti-inflammatory drug etodolac, and has anti-tumour activity in chronic lymphocytic leukaemia (CLL). SDX-308 and SDX-309 are more potent, structurally related indole-pyran analogues of SDX-101. The current study was performed to investigate and quantify the cytotoxic potentiating effects resulting from a combination of either SDX-101, SDX-308 or SDX-309 with standard cytotoxic agents used in the CLL treatment today. Methods: The lymphoma cell line U937-gtb was used, together with primary tumour cells isolated from seven CLL patients. Combinations between chlorambucil and each one of the agents etodolac, SDX-101, SDX-308 and SDX-309 were studied. In addition, SDX-309 was combined with fludarabine, doxorubicin or vincristine. Both simultaneous and sequential exposures were explored using the median-effect method. Results: Most combinations were additive, which could be of clinical benefit since SDX-101 has been shown to be well tolerated. At the 70% effect level, synergy was observed between SDX-308 and chlorambucil in U937-gtb cells and in two-third of the CLL samples. Since chlorambucil is the most important drug in CLL therapy today and SDX-308 is presently targeted as the lead clinical candidate, this combination would be interesting for further studies. Vincristine and SDX-309 were synergistic in two-fourth of CLL samples. Conclusions: To conclude, the non-COX-inhibiting etodolac-derivatives SDX-101, SDX-308 and SDX-309 are potential candidates for combination treatment of CLL. Especially, SDX-308 in combination with chlorambucil warrants further evaluation.
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- Schiesser, S., et al.
(författare)
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A Mild Synthesis of Aryl Triflates Enabling the Late-Stage Modification of Drug Analogs and Complex Peptides
- 2023
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Ingår i: Chemistry-a European Journal. - 0947-6539. ; 29:42
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Tidskriftsartikel (refereegranskat)abstract
- We report the discovery of a straightforward protocol to convert phenols into the corresponding aryl triflates using 1-methyl-3-((trifluoromethyl)sulfonyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one in the presence of a fluoride source. This novel reagent can be handled without any precautions to exclude air or moisture making this method highly convenient. The reactions generally show very clean conversions within only a few minutes at room temperature. The mild conditions allow the so far unprecedented O-triflation of tyrosine in peptides bearing challenging side chains present for example in arginine and histidine including the late-stage triflation of complex bioactive peptides. We show how aryl triflates - an interesting but so far underutilized group - can be used to optimize physicochemical and in vitro properties of compound series in medicinal chemistry. We believe that this method is highly attractive for applications in peptide functionalization as well as automated and medicinal chemistry.
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