Light-Based Printing of Leachable Salt Molds for Facile Shaping of Complex Structures

3D printing is a powerful manufacturing technology for shaping materials into complex structures. While the palette of printable materials continues to expand, the rheological and chemical requisites for printing are not always easy to fulfill. Here, a universal manufacturing platform is reported for shaping materials into intricate geometries without the need for their printability, but instead using light-based printed salt structures as leachable molds. The salt structures are printed using photocurable resins loaded with NaCl particles. The printing, debinding, and sintering steps involved in the process are systematically investigated to identify ink formulations enabling the preparation of crack-free salt templates. The experiments reveal that the formation of a load-bearing network of salt particles is essential to prevent cracking of the mold during the process. By infiltrating the sintered salt molds and leaching the template in water, complex-shaped architectures are created from diverse compositions such as biomedical silicone, chocolate, light metals, degradable elastomers, and fiber composites, thus demonstrating the universal, cost-effective, and sustainable nature of this new manufacturing platform.Aerospace Manufacturing Technologie

Structural basis of species-selective antagonist binding to the succinate receptor

The tricarboxylic acid cycle intermediate succinate is involved in metabolic processes and plays a crucial role in the homeostasis of mitochondrial reactive oxygen species. The receptor responsible for succinate signalling, SUCNR1 (also known as GPR91), is a member of the G-protein-coupled-receptor family and links succinate signalling to renin-induced hypertension, retinal angiogenesis and inflammation. Because SUCNR1 senses succinate as an immunological danger signal—which has relevance for diseases including ulcerative colitis, liver fibrosis, diabetes and rheumatoid arthritis—it is of interest as a therapeutic target. Here we report the high-resolution crystal structure of rat SUCNR1 in complex with an intracellular binding nanobody in the inactive conformation. Structure-based mutagenesis and radioligand-binding studies, in conjunction with molecular modelling, identified key residues for speciesselective antagonist binding and enabled the determination of the high-resolution crystal structure of a humanized rat SUCNR1 in complex with a high-affinity, humanselective antagonist denoted NF-56-EJ40. We anticipate that these structural insights into the architecture of the succinate receptor and its antagonist selectivity will enable structure-based drug discovery and will further help to elucidate the function of SUCNR1 in vitro and in vivo

Discovery And Optimization of Novel SUCNR1 Inhibitors: Design of Zwitterionic Derivatives with Salt-Bridge for Improvement of Oral Exposure

G-protein-coupled receptor SUCNR1 (succinate receptor 1 or GPR91) senses the citric cycle intermediate succinate and is implicated in various pathological conditions such as rheumatoid arthritis, liver fibrosis, or obesity. Here, we describe a novel SUCNR1 antagonist scaffold discovered by high-throughput screening. The poor permeation and absorption properties of the most potent compounds, which were zwitterionic in nature, could be improved by the formation of an internal salt bridge, which helped in shielding the two opposite charges and thus also the high polarity of zwitterions with separated charges. The designed compounds containing such a salt bridge reached high oral bioavailability and oral exposure. We believe that this principle could find a broad interest in the medicinal chemistry field as it can be useful not only for the modulation of properties in zwitterionic compounds but also in acidic or basic compounds with poor permeation