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Dr. Blijke S. Kroezen Gabriele Conti Benedetta Girardi Dr. Jonathan Cramer Dr. Xiaohua Jiang Dr. Said Rabbani Jennifer Müller Maja Kokot Enrico Luisoni Prof. Daniel Ricklin Dr. Oliver Schwardt Prof. Beat Ernst 《ChemMedChem》2020,15(18):1706-1719
Siglecs are members of the immunoglobulin gene family containing sialic acid binding N-terminal domains. Among them, Siglec-8 is expressed on various cell types of the immune system such as eosinophils, mast cells and weakly on basophils. Cross-linking of Siglec-8 with monoclonal antibodies triggers apoptosis in eosinophils and inhibits degranulation of mast cells, making Siglec-8 a promising target for the treatment of eosinophil- and mast cell-associated diseases such as asthma. The tetrasaccharide 6’-sulfo-sialyl Lewisx has been identified as a specific Siglec-8 ligand in glycan array screening. Here, we describe an extended study enlightening the pharmacophores of 6’-sulfo-sialyl Lewisx and the successful development of a high-affinity mimetic. Retaining the neuraminic acid core, the introduction of a carbocyclic mimetic of the Gal moiety and a sulfonamide substituent in the 9-position gave a 20-fold improved binding affinity. Finally, the residence time, which usually is the Achilles tendon of carbohydrate/lectin interactions, could be improved. 相似文献
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Jasmin Kuhn Philipp M. Klein Nader Al Danaf Joel Z. Nordin Sren Reinhard Dominik M. Loy Miriam Hhn Samir El Andaloussi Don C. Lamb Ernst Wagner Yoshitsugu Aoki Taavi Lehto Ulrich Lchelt 《Advanced functional materials》2019,29(48)
Phosphorodiamidate morpholino oligomers (PMOs) are oligonucleotide analogs that can be used for therapeutic modulation of pre‐mRNA splicing. Similar to other classes of nucleic acid‐based therapeutics, PMOs require delivery systems for efficient transport to the intracellular target sites. Here, artificial peptides based on the oligo(ethylenamino) acid succinyl‐tetraethylenpentamine (Stp), hydrophobic modifications, and an azide group are presented, which are used for strain‐promoted azide‐alkyne cycloaddition conjugation with splice‐switching PMOs. By systematically varying the lead structure and formulation, it is determined that the type of contained fatty acid and supramolecular assembly have a critical impact on the delivery efficacy. A compound containing linolenic acid with three cis double bonds exhibits the highest splice‐switching activity and significantly increases functional protein expression in pLuc/705 reporter cells in vitro and after local administration in vivo. Structural and mechanistic studies reveal that the lipopeptide PMO conjugates form nanoparticles, which accelerate cellular uptake and that the content of unsaturated fatty acids enhances endosomal escape. In an in vitro Duchenne muscular dystrophy exon skipping model using H2K‐mdx52 dystrophic skeletal myotubes, the highly potent PMO conjugates mediate significant splice‐switching at very low nanomolar concentrations. The presented aminoethylene‐lipopeptides are thus a promising platform for the generation of PMO‐therapeutics with a favorable activity/toxicity profile. 相似文献
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van Driel W.D. van Gils M.A.J. Xuejun Fan Zhang G.Q. Ernst L.J. 《Components and Packaging Technologies, IEEE Transactions on》2008,31(2):260-268
Exposed pad packages were introduced in the late 1980s and early 1990s because of their excellent thermal and electrical performance. Despite these advantages, the exposed pad packages experience a lot of thermo-hygro-mechanical related reliability problems during qualification and testing. Examples are die lift, which occurs predominantly after moisture sensitivity level conditions, and die-attach to leadframe delamination leading to downbond stitch breaks during temperature cycling. In this chapter, nonlinear finite element (FE) models using fracture mechanics based J-integral calculations are used to assess the reliability problems of the exposed pad package family. Using the parametric FE models any geometrical and material effects can be explored to their impact on the occurrence diepad delamination, and dielift. For instance the impact of diepad size is found to be of much less importance as the impact of die thickness is. Using the fracture mechanics approach, the starting location for the delamination from thermo-hygro-mechanical point of view is deducted. The results indicate that when diepad delamination is present, cracks are likely to grow beneath the die and dielift will occur. The interaction between dielift and other failure modes, such as lifted ball bonds, are not found to be very significant. The FE models are combined with simulation-based optimization methods to deduct design guidelines for optimal reliability of the exposed pad family. 相似文献
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Ernst L.J. Hinman W.L. Quam D.H. Thorp J.S. 《Power Delivery, IEEE Transactions on》1992,7(4):1834-1852
The authors describe the relaying concepts of charge comparison. Charge comparison is a new transmission line protection system. It is a form of current differential relaying. Charge comparison largely resolves the traditional problems of current differential relaying of transmission lines, which are that protection is lost if a channel fails, a large channel capacity is required, and precise channel delay compensation is required. This technique is suitable for the protection of two- or three-terminal AC transmission lines, of all lengths and voltage levels, with or without series of shunt compensation, with three-hole or single-pole tripping 相似文献