3 research outputs found
Rational design of an DNA-scaffolded high-affinity binder for langerin
Binders of Langerin could target vaccines to Langerhans cells for improved therapeutic effect. As Langerin has only low affinity for monovalent glycan ligands, highly multivalent presentation has previously been key for targeting. Aiming to reduce the amount of ligands required, we rationally designed molecularly defined high affinity binders based on the precise display of glycomimetic ligands (Glc2NTs) on DNA-PNA scaffolds. Rather than mimicking Langerin?s homotrimeric structure with a C3-symmetrical scaffold, we devised a strategy to improve readily accessible, easy to design bivalent binders. The method considers the requirements for bridging sugar binding sites and statistical rebinding as a means to both strengthen the interactions at single binding sites and amplify the avidity enhancement provided by chelation. The method enabled a 1150-fold net improvement over the affinity of the free ligand and provided a nanomolar binder (IC50 = 300 nM) for specific internalization by Langerin expressing cells
Rational Design of a DNAâScaffolded HighâAffinity Binder for Langerin
Binders of langerin could target vaccines to Langerhans cells for improved therapeutic effect. Since langerin has low affinity for monovalent glycan ligands, highly multivalent presentation has previously been key for targeting. Aiming to reduce the amount of ligand required, we rationally designed molecularly defined highâaffinity binders based on the precise display of glycomimetic ligands (Glc2NTs) on DNAâPNA scaffolds. Rather than mimicking langerin's homotrimeric structure with a C3âsymmetric scaffold, we developed readily accessible, easyâtoâdesign bivalent binders. The method considers the requirements for bridging sugar binding sites and statistical rebinding as a means to both strengthen the interactions at single binding sites and amplify the avidity enhancement provided by chelation. This gave a 1150âfold net improvement over the affinity of the free ligand and provided a nanomolar binder (IC50=300â
nM) for specific internalization by langerinâexpressing cells.Peer Reviewe
Exploring disease-causing traits for drug repurposing in critically ill COVID-19 patients:A causal inference approach
Despite recent development of vaccines to prevent SARS-CoV-2 infection, treatment of critically ill COVID-19 patients remains an important goal. In principle, genome-wide association studies (GWASs) provide a shortcut to the clinical evidence needed to repurpose existing drugs; however, genes identified frequently lack a causal disease link. We report an alternative method for finding drug repurposing targets, focusing on disease-causing traits beyond immediate disease genetics. Sixty blood cell types and biochemistries, and body mass index, were screened on a cohort of critically ill COVID-19 cases and controls that exhibited mild symptoms after infection, yielding high neutrophil cell count as a possible causal trait for critical illness. Our methodology identified CDK6 and janus kinase (JAK) inhibitors as treatment targets that were validated in an ex vivo neutrophil extracellular trap (NET) formation assay. Our methodology demonstrates the increased power for drug target identification by leveraging large disease-causing trait datasets.</p