| 1. |
- Bossart, Martin, et al.
(författare)
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Effects on weight loss and glycemic control with SAR441255, a potent unimolecular peptide GLP-1/GIP/GCG receptor triagonist
- 2022
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Ingår i: Cell Metabolism. - : CELL PRESS. - 1550-4131 .- 1932-7420. ; 34:1, s. 59-
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Tidskriftsartikel (refereegranskat)abstract
- Unimolecular triple incretins, combining the activity of glucagon-like peptide-1 (GLP-1), glucose -dependent insulinotropic polypeptide (GIP), and glucagon (GCG), have demonstrated reduction in body weight and improved glucose control in rodent models. We developed SAR441255, a synthetic peptide agonist of the GLP-1, GCG, and GIP receptors, structurally based on the exendin-4 sequence. SAR441255 displays high potency with balanced activation of all three target receptors. In animal models, metabolic outcomes were superior to results with a dual GLP-1/GCG receptor agonist. Preclinical in vivo positron emission tomography imaging demonstrated SAR441255 binding to GLP-1 and GCG receptors. In healthy subjects, SAR441255 improved glycemic control during a mixed-meal tolerance test and impacted biomarkers for GCG and GIP receptor activation. Single doses of SAR441255 were well tolerated. The results demonstrate that integrating GIP activity into dual GLP-1 and GCG receptor agonism provides improved effects on weight loss and glycemic control while buffering the diabetogenic risk of chronic GCG receptor agonism.
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| 2. |
- Eriksson, Olof, et al.
(författare)
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Drug Occupancy Assessment at the Glucose-Dependent Insulinotropic Polypeptide Receptor by Positron Emission Tomography
- 2021
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Ingår i: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 70:4, s. 842-853
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Tidskriftsartikel (refereegranskat)abstract
- Targeting of the glucose-dependent insulinotropic polypeptide receptor (GIPR) is an emerging strategy in antidiabetic drug development. The aim of this study was to develop a positron emission tomography (PET) radioligand for the GIPR to enable the assessment of target distribution and drug target engagement in vivo. The GIPR-selective peptide S02-GIP was radiolabeled with Ga-68. The resulting PET tracer [Ga-68]S02-GIP-T4 was evaluated for affinity and specificity to human GIPR (huGIPR). The in vivo GIPR binding of [Ga-68]S02-GIP-T4 as well as the occupancy of a drug candidate with GIPR activity were assessed in nonhuman primates (NHPs) by PET. [Ga-68]S02-GIP-T4 bound with nanomolar affinity and high selectivity to huGIPR in overexpressing cells. In vivo, pancreatic binding in NHPs could be dose-dependently inhibited by coinjection of unlabeled S02-GIP-T4. Finally, subcutaneous pretreatment with a high dose of a drug candidate with GIPR activity led to a decreased pancreatic binding of [Ga-68]S02-GIP-T4, corresponding to a GIPR drug occupancy of almost 90%. [Ga-68]S02-GIP-T4 demonstrated a safe dosimetric profile, allowing for repeated studies in humans. In conclusion, [Ga-68]S02-GIP-T4 is a novel PET biomarker for safe, noninvasive, and quantitative assessment of GIPR target distribution and drug occupancy.
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| 3. |
- Gad, Helge, et al.
(författare)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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| 4. |
- Jager, Nicolas W., et al.
(författare)
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Transforming European Water Governance? : Participation and River Basin Management under the EU Water Framework Directive in 13 Member States
- 2016
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Ingår i: Water. - : MDPI AG. - 2073-4441. ; 8:4
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Tidskriftsartikel (refereegranskat)abstract
- The European Union (EU) Water Framework Directive (WFD) requires EU member states to produce and implement river basin management plans, which are to be designed and updated via participatory processes that inform, consult with, and actively involve all interested stakeholders. The assumption of the European Commission is that stakeholder participation, and institutional adaptation and procedural innovation to facilitate it, are essential to the effectiveness of river basin planning and, ultimately, the environmental impact of the Directive. We analyzed official documents and the WFD literature to compare implementation of the Directive in EU member states in the initial WFD planning phase (2000-2009). Examining the development of participatory approaches to river basin management planning, we consider the extent of transformation in EU water governance over the period. Employing a mixed quantitative and qualitative approach, we map the implementation "trajectories" of 13 member states, and then provide a detailed examination of shifts in river basin planning and participation in four member states (Germany, Sweden, Poland and France) to illustrate the diversity of institutional approaches observed. We identify a general tendency towards increased, yet circumscribed, stakeholder participation in river basin management in the member states examined, alongside clear continuities in terms of their respective pre-WFD institutional and procedural arrangements. Overall, the WFD has driven a highly uneven shift to river basin-level planning among the member states, and instigated a range of efforts to institutionalize stakeholder involvement-often through the establishment of advisory groups to bring organized stakeholders into the planning process.
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| 5. |
- Maslyuk, Volodymyr V., et al.
(författare)
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Organometallic benzene-vanadium wire : A one-dimensional half-metallic ferromagnet
- 2006
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Ingår i: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 97:9, s. 097201-
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Tidskriftsartikel (refereegranskat)abstract
- Using density functional theory we perform theoretical investigations of the electronic properties of a freestanding one-dimensional organometallic vanadium-benzene wire. This system represents the limiting case of multidecker V-n(C6H6)(n+1) clusters which can be synthesized with established methods. We predict that the ground state of the wire is a 100% spin-polarized ferromagnet (half-metal). Its density of states is metallic at the Fermi energy for the minority electrons and shows a semiconductor gap for the majority electrons. We find that the half-metallic behavior is conserved up to 12% longitudinal elongation of the wire. Ab initio electron transport calculations reveal that finite size vanadium-benzene clusters coupled to ferromagnetic Ni or Co electrodes will work as nearly perfect spin filters.
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| 6. |
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| 7. |
- Nyberg, Lars, 1962-, et al.
(författare)
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Sustainability aspects of water regulation and flood risk reduction in Lake Vänern
- 2014
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Ingår i: Aquatic Ecosystem Health & Management. - : Taylor & Francis. - 1463-4988 .- 1539-4077. ; 17:4, s. 331-340
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Tidskriftsartikel (refereegranskat)abstract
- A modern feature of flood risk management is to integrate ecological, economic and social aspects in risk prevention and mitigation. Risk-reducing measures can be in conflict with ecosystem functions and complicate upstream/downstream relations. Flood risks are also influenced by processes in the catchment, such as changes in climate and land-use, or increases of vulnerable urban areas. Lake Vänern in Sweden has high ecological and social values but is also flood-prone, which in this article has been analyzed from a perspective of sustainable development. Lake Vänern and the Göta älv River are used for drinking water supply, shipping, hydropower production, fishing, tourism, as a recipient for industries and wastewater plants, etc. The flood risks are connected to landslide and industrial risks. One interest at stake is the drinking water supply for 800,000 persons in the Gothenburg region. According to climate scenarios, flood risks will increase in the 21st century due to increased precipitation. Recent studies in the region were used to identify relevant interests and values connected to Lake Vänern. The study reveals differing interests in relation to water level regimes. From a flood protection perspective (risks around the lake and downstream to Gothenburg) a low and stable water level is beneficial. For shipping and hydropower, a stable medium-high water level is wanted, whereas from an ecosystem and landscape development perspective larger water level amplitudes are optimal. One out of a few reasons for this is the need to prevent a massive increase in vegetation in coastal areas. There are good reasons to have a broad decision-support, representing different values and interests, when the permanent water regulation scheme will be decided. This study also addresses the potential to reconcile the concept of flood risk management with that of a sustainable development.
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| 8. |
- Sigmund, Gabriel, et al.
(författare)
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Broaden chemicals scope in biodiversity targets
- 2022
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 376:6599, s. 1279-1280
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 9. |
- Velikyan, Irina, 1966-, et al.
(författare)
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First-in-class positron emission tomography tracer for the glucagon receptor
- 2019
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Ingår i: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- The glucagon receptor (GCGR) is emerging as an important target in anti-diabetic therapy, especially as part of the pharmacology of dual glucagon-like peptide-1/glucagon (GLP-1/GCG) receptor agonists. However, currently, there are no suitable biomarkers that reliably demonstrate GCG receptor target engagement.Methods: Two potent GCG receptor peptide agonists, S01-GCG and S02-GCG, were labeled with positron emission tomography (PET) radionuclide gallium-68. The GCG receptor binding affinity and specificity of the resulting radiopharmaceuticals [68Ga]Ga-DO3A-S01-GCG and [68Ga]Ga-DO3A-S02-GCG were evaluated in HEK-293 cells overexpressing the human GCG receptor and on frozen hepatic sections from human, non-human primate, and rat. In in vivo biodistribution, binding specificity and dosimetry were assessed in rat.Results: [68Ga]Ga-DO3A-S01-GCG in particular demonstrated GCG receptor-mediated binding in cells and liver tissue with affinity in the nanomolar range required for imaging. [68Ga]Ga-DO3A-S01-GCG binding was not blocked by co-incubation of a GLP-1 agonist. In vivo binding in rat liver was GCG receptor specific with low non-specific binding throughout the body. Moreover, the extrapolated human effective doses, predicted from rat biodistribution data, allow for repeated PET imaging potentially also in combination with GLP-1R radiopharmaceuticals.Conclusion: [68Ga]Ga-DO3A-S01-GCG thus constitutes a first-in-class PET tracer targeting the GCG receptor, with suitable properties for clinical development. This tool has potential to provide direct quantitative evidence of GCG receptor occupancy in humans.
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