@article{FrickeFrometaKerkhoffetal.2025, author = {Fricke, Mackenzie S. and Frometa, Magalee R. and Kerkhoff, Yannic and Bernhard, Samuel P. and Tahir, Ramat S. and Quaas, Elisa and Totten, William H. and Haag, Rainer and Achazi, Katharina and Cloninger, Mary J.}, title = {The toxicity, uptake, and impact on galectin-3 mediated apoptosis of lactose functionalized PAMAM dendrimers}, volume = {6}, journal = {Materials Advances}, doi = {10.1039/D4MA00782D}, pages = {3171 -- 3184}, year = {2025}, abstract = {Poly(amidoamine) (PAMAM) dendrimers functionalized with ligands that are designed to interact with biological receptors are important macromolecules for the elucidation and mediation of biological recognition processes. Specifically, carbohydrate functionalized dendrimers are useful synthetic multivalent systems for the study of multivalent protein-carbohydrate interactions. For example, lactose functionalized glycodendrimers can be used to discern the function of galectins, galactoside-binding proteins that are often over-expressed during cancer progression. In order to effectively interpret cancer cellular assays using glycodendrimers, however, their properties in the presence of cells must first be assessed. Macromolecules that are taken up by cells would be expected to have access to many different cell signaling pathways and modes of action that solely extracellular macromolecules cannot utilize. In addition, macromolecules that display cellular toxicity could not be used as drug delivery vehicles. Here, we report fundamental studies of cellular toxicity, viability, and uptake with four generations of lactose functionalized PAMAM dendrimers. In all cases, the dendrimers are readily taken up by the cells but do not display any significant cellular toxicity. The glycodendrimers also increase cellular apoptosis, suggesting that they may abrogate the antiapoptotic protections afforded by galectin-3 to cancer cells. The results reported here indicate that appropriately functionalized PAMAM dendrimers can be used as nontoxic tools for the study and mediation of both extra and intracellular cancer processes.}, language = {en} } @article{KhatriBobackAbdelwahabetal.2025, author = {Khatri, Vinod and Boback, Nico and Abdelwahab, Hassan and Niemeyer, Daniela and Palmer, Tahlia M. and Sahoo, Anil Kumar and Kerkhoff, Yannic and Ludwig, Kai and Balci, Dilara and Trimpert, Jakob and Haag, Rainer and Povolotsky, Tatyana L. and Netz, Roland R. and Drosten, Christian and Lauster, Daniel C. and Bhatia, Sumati}, title = {Polysialosides outperform sulfated analogs for the inhibition of SARS-CoV-2}, volume = {21}, journal = {Small}, number = {34}, doi = {10.1002/smll.202500719}, year = {2025}, abstract = {Both polysialosides and polysulfates are known to interact with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. However, a comprehensive site by site analysis of their binding affinities and potential synergistic antiviral effects have not been performed. Here, we report on the synthesis of polysialosides with nanomolar binding affinities to spike proteins of SARS-CoV-2 in solution using microscale thermophoresis (MST). The dendritic polyglycerol based polysialosides dPG500(SA)0.55 and dPG500(SA)0.25, with a dissociation constant Kd of 4.78 nM and 10.85 nM, respectively, bind ~500 times stronger than the high density polysulfated analog dPG500(OSO3Na)0.55, to intact SARS-CoV-2 virus particles or isolated spike protein. In fact, the presence of sulfate groups in a heteromultivalent compound dPG500(SA)0.20(OSO3Na)0.20 weakens the binding to spike proteins. A polycarboxylated analog does not bind to SARS-CoV-2, ruling out that the interaction of polysialoside is simply driven by electrostatic interactions. Furthermore, we found potent nanomolar binding of dPG500(SA)0.55 to SARS-CoV-2 variant B.1.617 (Delta) and B.1.1.529 (Omicron) RBD. Using explicit-solvent all-atom molecular dynamics (MD) simulations and docking studies, we obtain atomistic details on the interaction of different functional groups with the SARS-CoV-2 RBD and their binding affinities. Our data support the conclusion that sialosides interact stronger with RBD than sulfates. Notably, our most affine binder dPG500(SA)0.55 inhibits SARS-CoV-2 (WT, D614G) replication up to 98.6\% at low nanomolar concentrations.}, language = {en} }