The efficacy of therapeutic antibodies that induce antibody-dependent cellular cytotoxicity can be improved by reduced fucosylation. Consequently, fucosylation is a critical product attribute of monoclonal antibodies produced as protein therapeutics. Small molecule fucosylation inhibitors have also shown promise as potential therapeutics in animal models of tumors, arthritis, and sickle cell disease. Potent small molecule metabolic inhibitors of cellular protein fucosylation, 6,6,6-trifluorofucose per-O-acetate and 6,6,6-trifluorofucose (fucostatin I), were identified that reduces the fucosylation of recombinantly expressed antibodies in cell culture in a concentration-dependent fashion enabling the controlled modulation of protein fucosylation levels. 6,6,6-Trifluorofucose binds at an allosteric site of GDP-mannose 4,6-dehydratase (GMD) as revealed for the first time by the X-ray cocrystal structure of a bound allosteric GMD inhibitor. 6,6,6-Trifluorofucose was found to be incorporated in place of fucose at low levels (<1%) in the glycans of recombinantly expressed antibodies. A fucose-1-phosphonate analog, fucostatin II, was designed that inhibits fucosylation with no incorporation into antibody glycans, allowing the production of afucosylated antibodies in which the incorporation of non-native sugar is completely absent-a key advantage in the production of therapeutic antibodies, especially biosimilar antibodies. Inhibitor structure-activity relationships, identification of cellular and inhibitor metabolites in inhibitor-treated cells, fucose competition studies, and the production of recombinant antibodies with varying levels of fucosylation are described.
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http://dx.doi.org/10.1021/acschembio.6b00460 | DOI Listing |
J Phys Chem B
January 2025
College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China.
Reline, which is composed of choline chloride and urea in a molar ratio of 1:2, is the first and most extensively studied deep eutectic solvent (DES). In certain applications, reline is blended with organic solvents, dimethyl sulfoxide (DMSO) in most cases, to gain improved properties. Therefore, it is crucial to have a profound understanding of the impact of DMSO on the dynamics and structures of the species in the binary mixtures.
View Article and Find Full Text PDFJ Phys Chem Lett
January 2025
Department of Chemistry, Anhui University, Hefei 230601, P. R. China.
Despite being studied for almost two centuries, aromaticity has always been a controversial concept. We previously proposed a unified aromatic rule for π-conjugated systems by two-dimensional (2D) superatomic-molecule theory, where benzenoid rings are treated as period 2 2D superatoms (3π-N, 4π-O, 5π-F, 6π-Ne) and, further, bond to form 2D superatomic molecules. Herein, to build a 2D periodic table, we further extend the theory to period 3 (7π-P, 8π-S, 9π-Cl, 10π-Ar) and period 1 (1π-H, 2π-He) elements.
View Article and Find Full Text PDFPLoS One
January 2025
SLAC National Accelerator Laboratory, Stanford University, Stanford, California, United States of America.
Protein-Protein Interactions (PPIs) are a key interface between virus and host, and these interactions are important to both viral reprogramming of the host and to host restriction of viral infection. In particular, viral-host PPI networks can be used to further our understanding of the molecular mechanisms of tissue specificity, host range, and virulence. At higher scales, viral-host PPI screening could also be used to screen for small-molecule antivirals that interfere with essential viral-host interactions, or to explore how the PPI networks between interacting viral and host genomes co-evolve.
View Article and Find Full Text PDFSci Adv
January 2025
Department of Chemical Physiology & Biochemistry, Oregon Health & Science University, Portland, OR 97239, USA.
P2X receptors (P2XRs) are adenosine 5'-triphosphate (ATP)-gated ion channels comprising homomeric and heteromeric trimers of seven subtypes (P2X1-P2X7) that confer different rates of desensitization. The helical recoil model of P2XR desensitization proposes stability of the cytoplasmic cap sets the rate of desensitization, but timing of its formation is unclear for slow-desensitizing P2XRs. We report cryo-electron microscopy structures of full-length wild-type human P2X4 receptor in apo closed, antagonist-bound inhibited, and ATP-bound desensitized states.
View Article and Find Full Text PDFJ Phys Chem A
January 2025
Department of Chemistry and Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Collaborative Innovation Center of Chemistry for Energy Materials (iChEM), Fudan University, Shanghai 200438, China.
Understanding the interactions between transition metal atoms and molecules is important for the study of various related chemical and physical processes. In this study, we have investigated collisions between iron (Fe), iridium (Ir), and platinum (Pt) and the small molecules CH, O, and CO using a crossed-beam and time-sliced ion velocity map imaging technique. Elastic collisions were observed in all cases, except for collisions of Pt with O and CO.
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