Lipid nanoparticle-mediated mRNA delivery to CD34 cells in rhesus monkeys.

Transplantation of ex vivo engineered hematopoietic stem cells (HSCs) can lead to robust clinical responses but carries risks of adverse events from bone marrow mobilization, chemotherapy conditioning and other factors. HSCs have been modified in vivo using lipid nanoparticles (LNPs) decorated with targeting moieties, which increases manufacturing complexity. Here we screen 105 LNPs without targeting ligands for effective homing to the bone marrow in mouse.

Multivalent Targeting of the Asialoglycoprotein Receptor by Virus-Like Particles.

The asialoglycoprotein receptor (ASGPR) is expressed in high density on hepatocytes. Multivalent variants of galactosyl carbohydrates bind ASGPR with high affinity, enabling hepatic delivery of ligand-bound cargo. Virus-like particle (VLP) conjugates of a relatively high-affinity ligand were efficiently endocytosed by ASGPR-expressing cells in a manner strongly dependent on the nature and density of ligand display, with the best formulation using a nanomolar-, but not a picomolar-level, binder.

Total Synthesis of the Repeating Units of -Specific Polysaccharide of subsp. UCM B-306 via One-Pot Glycosylation.

Herein we report the first total syntheses of the trisaccharide-repeating units of subsp. UCM B-306 via a one-pot assembly of the core trisaccharide structure. The rare-sugar-containing trisaccharide-repeating units are comprised of d-bacillosamine, 2-amino-2-deoxy-d-galacturonic acid or amide, and d-rhamnose units linked through three consecutive α-linkages.

Total Synthesis of the Repeating Unit of Zwitterionic Polysaccharide A1.

Zwitterionic polysaccharides isolated from commensal bacteria are endowed with unique immunological properties and are emerging as immunotherapeutic agents as well as vaccine carriers. Reported herein is a total synthesis of the repeating unit of zwitterionic polysaccharide A1 (PS A1). The structurally complex tetrasaccharide unit contains a rare sugar 2-acetamido-4-amino-2,4,6-trideoxy-d-galactose (AAT) and two consecutive 1,2- glycosidic linkages.

Design, Synthesis, and Biological Investigation of Thailanstatin A and Spliceostatin D Analogues Containing Tetrahydropyran, Tetrahydrooxazine, and Fluorinated Structural Motifs.

Thailanstatin A and spliceostatin D, two naturally occurring molecules endowed with potent antitumor activities by virtue of their ability to bind and inhibit the function of the spliceosome, and their natural siblings and designed analogues, constitute an appealing family of compounds for further evaluation and optimization as potential drug candidates for cancer therapies. In this article, the design, synthesis, and biological investigation of a number of novel thailanstatin A analogues, including some accommodating 1,1-difluorocyclopropyl and tetrahydrooxazine structural motifs within their structures, are described. Important findings from these studies paving the way for further investigations include the identification of several highly potent compounds for advancement as payloads for antibody-drug conjugates (ADCs) as potential targeted cancer therapies and/or small molecule drugs, either alone or in combination with other anticancer agents.

Total Synthesis of the Lipid-Anchor-Attached Core Trisaccharides of Lipoteichoic Acids of and Uo5.

Herein we report an efficient total synthesis of lipid-anchor-appended core trisaccharides of lipoteichoic acids of and Uo5. The key features include the expedient synthesis of the rare sugar 2,4,6-trideoxy-2-acetamido-4-amino-d-Galp building block via one-pot sequential S2 reactions and the α-selective coupling of d-thioglucoside with the diacyl glycerol acceptor to construct a common disaccharide acceptor, which was utilized in the total synthesis of target molecules and .

"One-Pot" Protection, Glycosylation, and Protection-Glycosylation Strategies of Carbohydrates.

Carbohydrates, which are ubiquitously distributed throughout the three domains of life, play significant roles in a variety of vital biological processes. Access to unique and homogeneous carbohydrate materials is important to understand their physical properties, biological functions, and disease-related features. It is difficult to isolate carbohydrates in acceptable purity and amounts from natural sources.

Total Synthesis of Repeating Unit of O-Polysaccharide of Providencia alcalifaciens O22 via One-Pot Glycosylation.

The first total synthesis of the phosphorylated trisaccharide repeating unit of Providencia alcalifaciens O22 is reported. The trisaccharide contains rare deoxyamino sugar AAT at the reducing end and d-glyceramide 2-phosphate at the other end. The efficient synthesis involves one-pot assembly of trisaccharide and late-stage phosphorylation as key steps.

Assembling Glycan-Charged Dolichol Phosphates: Chemoenzymatic Synthesis of a Haloferax volcanii N-Glycosylation Pathway Intermediate.

N-glycosylation, the covalent attachment of glycans to select protein target Asn residues, is a post-translational modification performed by all three domains of life. In the halophilic archaea Haloferax volcanii, in which understanding of this universal protein-processing event is relatively well-advanced, genes encoding the components of the archaeal glycosylation (Agl) pathway responsible for the assembly and attachment of an N-linked pentasaccharide have been identified. As elsewhere, the N-linked glycan is assembled on phosphodolichol carriers before transfer to target Asn residues.

Development of Rare Bacterial Monosaccharide Analogs for Metabolic Glycan Labeling in Pathogenic Bacteria.

Bacterial glycans contain rare, exclusively bacterial monosaccharides that are frequently linked to pathogenesis and essentially absent from human cells. Therefore, bacterial glycans are intriguing molecular targets. However, systematic discovery of bacterial glycoproteins is hampered by the presence of rare deoxy amino sugars, which are refractory to traditional glycan-binding reagents.

First synthesis of Bacillus cereus Ch HF-PS cell wall trisaccharide repeating unit.

The first total synthesis of Ch HF-PS, a cell wall trisaccharide repeating unit of B. cereus, is reported. The synthetic trisaccharide is appended with an aminopropyl linker at the reducing end to allow for conjugation to proteins and microarrays.