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- Gising, Johan, 1981-, et al.
(författare)
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The Discovery of New Inhibitors of Insulin-Regulated Aminopeptidase by a High-Throughput Screening of 400,000 Drug-like Compounds
- 2024
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 25:7
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Tidskriftsartikel (refereegranskat)abstract
- With the ambition to identify novel chemical starting points that can be further optimized into small drug-like inhibitors of insulin-regulated aminopeptidase (IRAP) and serve as potential future cognitive enhancers in the clinic, we conducted an ultra-high-throughput screening campaign of a chemically diverse compound library of approximately 400,000 drug-like small molecules. Three biochemical and one biophysical assays were developed to enable large-scale screening and hit triaging. The screening funnel, designed to be compatible with high-density microplates, was established with two enzyme inhibition assays employing either fluorescent or absorbance readouts. As IRAP is a zinc-dependent enzyme, the remaining active compounds were further evaluated in the primary assay, albeit with the addition of zinc ions. Rescreening with zinc confirmed the inhibitory activity for most compounds, emphasizing a zinc-independent mechanism of action. Additionally, target engagement was confirmed using a complementary biophysical thermal shift assay where compounds causing positive/negative thermal shifts were considered genuine binders. Triaging based on biochemical activity, target engagement, and drug-likeness resulted in the selection of 50 qualified hits, of which the IC50 of 32 compounds was below 3.5 µM. Despite hydroxamic acid dominance, diverse chemotypes with biochemical activity and target engagement were discovered, including non-hydroxamic acid compounds. The most potent compound (QHL1) was resynthesized with a confirmed inhibitory IC50 of 320 nM. Amongst these compounds, 20 new compound structure classes were identified, providing many new starting points for the development of unique IRAP inhibitors. Detailed characterization and optimization of lead compounds, considering both hydroxamic acids and other diverse structures, are in progress for further exploration.
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| 2. |
- Troell, Max, 1962-, et al.
(författare)
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Perspectives on aquaculture's contribution to the Sustainable Development Goals for improved human and planetary health
- 2023
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Ingår i: Journal of the World Aquaculture Society. - 0893-8849 .- 1749-7345. ; 54:2, s. 251-342
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Forskningsöversikt (refereegranskat)abstract
- The diverse aquaculture sector makes important contributions toward achieving the Sustainable Development Goals (SDGs)/Agenda 2030, and can increasingly do so in the future. Its important role for food security, nutrition, livelihoods, economies, and cultures is not clearly visible in the Agenda 21 declaration. This may partly reflect the state of development of policies for aquaculture compared with its terrestrial counterpart, agriculture, and possibly also because aquaculture production has historically originated from a few key hotspot regions/countries. This review highlights the need for better integration of aquaculture in global food system dialogues. Unpacking aquaculture's diverse functions and generation of values at multiple spatiotemporal scales enables better understanding of aquaculture's present and future potential contribution to the SDGs. Aquaculture is a unique sector that encompasses all aquatic ecosystems (freshwater, brackish/estuarine, and marine) and is also tightly interconnected with terrestrial ecosystems through, for example, feed resources and other dependencies. Understanding environmental, social, and economic characteristics of the multifaceted nature of aquaculture provides for more context-specific solutions for addressing both opportunities and challenges for its future development. This review includes a rapid literature survey based on how aquaculture links to the specific SDG indicators. A conceptual framework is developed for communicating the importance of context specificity related to SDG outcomes from different types of aquaculture. The uniqueness of aquaculture's contributions compared with other food production systems are discussed, including understanding of species/systems diversity, the role of emerging aquaculture, and its interconnectedness with supporting systems. A selection of case studies is presented to illustrate: (1) the diversity of the aquaculture sector and what role this diversity can play for contributions to the SDGs, (2) examples of methodologies for identification of aquaculture's contribution to the SDGs, and (3) trade-offs between farming systems' contribution to meeting the SDGs. It becomes clear that decision-making around resource allocation and trade-offs between aquaculture and other aquatic resource users needs review of a wide range of established and emergent systems. The review ends by highlighting knowledge gaps and pathways for transformation that will allow further strengthening of aquaculture's role for contributing to the SDGs. This includes identification and building on already existing monitoring that can enable capturing SDG-relevant aquaculture statistics at a national level and discussion of how a cohesive and comprehensive aquaculture strategy, framed to meet the SDGs, may help countries to prioritize actions for improving well-being.
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