Peter H. Seeberger

Chemical synthesis of oligosaccharides is a critical tool to study the biological functions of glycans. To accelerate glycan synthesis, automated glycan assembly (AGA) was introduced 25 years ago. However, major chemical databases such as SciFinder and Reaxys do not accurately index these automated syntheses, leaving more than two decades of reaction data out of reach for both synthetic chemists and data-driven tools. Herein, we report the AGA Companion, a curated, comprehensive database with accompanying search tools that offers closeto-full coverage of all glycans and their glycosylation parameters produced through AGA. An analysis of the full dataset provides the first systematic overview of solid-phase glycan assembly, reveals hidden trends in glycosylation and aids future problem selection, thereby laying a foundation for new synthetic endeavours and a data-driven approach to automated glycan assembly.

Accurately defining glycosidase specificity is often limited by access to well‐defined oligosaccharide probes and analytical tools capable of resolving regioisomers at low concentrations. We synthesized two linear and one branched glycogen‐mimetic tetrasaccharides, bearing exclusively 1,2‐ cis , namely α‐1,4 or α‐1,6 linkages using a reagent‐controlled stereoselective glycosylation strategy. Their enzymatic degradation by Homo sapiens glycogen debranching enzyme ( Hs GDE) and two commercial α‐1,4‐glucosidases was assessed by hydrophilic interaction liquid chromatography‐mass spectrometry and high‐resolution cyclic ion mobility mass spectrometry (cIMS‐MS), enabling separation and quantification of substrates and products in the micromolar range. Hs GDE selectively cleaved the α‐1,6‐branch while showing low activity on terminal α‐1,6 linkages. The Saccharomyces cerevisiae α‐1,4‐glucosidase showed high α‐1,4 selectivity, whereas the rice enzyme displayed broad promiscuity toward all regioisomers. The cIMS‐MS provided rapid baseline separation of the synthetic tetrasaccharides and confirmed the absence of inhibition by nonsubstrate isomers. This integrated synthetic‐analytical workflow offers an efficient platform for rapid annotation of glycosidase specificity and mechanistic studies in glycogen metabolism.

A predictive framework enables rational selection of flow rate, concentration, and reaction time in solid-phase flow reactors.

Photoredox catalysis offers powerful opportunities for organic synthesis, yet its broader application remains limited by the difficulty of identifying viable synthetic routines and conditions. Here, we present an experimentally validated, machine-learning-assisted workflow that combines literature-precedent retrieval with reaction-condition recommendation to support chemist-guided design of photoredox transformations. With 11,069 curated literature-derived reaction records, a variational autoencoder organizes photoredox reactions in a learned latent space to enable reaction-space navigation and retrieval of traceable synthetic precedents, while random-forest classifiers recommend feasible catalyst and reagent classes for proposed reactant–product pairs. External validation on unseen literature examples and experimental validation of selected model-guided proposals demonstrates the practical utility of the workflow. It further enabled three unreported photoredox transformations, highlighting its possibility for generating experimentally testable synthetic hypotheses.

Atomic hydrogen (H•), the union of an electron and a proton, is the smallest radical of the universe. Over the past century, advanced techniques such as electric discharge and mercury UV sensitization enabled a fundamental understanding of the reactivity of H• but fell short of providing synthetic methods to exploit its intriguing properties. Here we report a light-mediated method to access hydrogen radicals under synthetically useful conditions. This strategy enabled the mild, metal-free reduction of highly functionalized alkenes and halides. Mechanistic, EPR, and DFT studies suggest hydrogen radical generation via a Rydberg radical intermediate, with potential applications across the chemical and biological sciences.

Hepatocellular carcinoma (HCC) remains highly lethal due to a complex tumor microenvironment (TME) that limits therapeutic efficacy. Herein, a dual‐targeted nanotherapeutic platform (SC@GRT‐COF‐366) based on a covalent organic framework (COF‐366) is reported for synergistic HCC treatment. This multifunctional system integrates chemotherapy, photodynamic therapy, autophagy regulation, and TME remodeling to synergistically inhibit tumor metastasis. Gal‐D5HT‐modified nanoparticles achieve enhanced HCC targeting via myeloperoxidase (MPO)‐responsive aggregation in the inflammatory microenvironment and ASGPR‐mediated uptake. Upon light irradiation, COF‐366 generates singlet oxygen to induce tumor cell apoptosis and simultaneously enhances MPO expression and neutrophil infiltration, further amplifying MPO‐triggered nanoparticle aggregation and establishing a self‐amplifying retention‐therapy cascade. Meanwhile, co‐loaded sorafenib and chloroquine enable combined chemotherapy and autophagy inhibition, effectively overcoming drug resistance. In vivo results demonstrate significantly enhanced and prolonged tumor accumulation compared with single‐targeted systems, resulting in a tumor growth inhibition rate of 93.5 ± 1.02% in subcutaneous models and effective suppression of lung metastasis in orthotopic HCC models. Notably, treatment markedly reduces neutrophil extracellular traps (NETs) formation, indicating favorable remodeling of the tumor immune microenvironment. Collectively, this multifunctional COF‐based nanoplatform integrates dual‐targeted delivery, amplified tumor retention, and synergistic multimodal therapy, offering a promising strategy for advanced HCC treatment.

ZUSAMMENFASSUNG: Die dynamische Glykan‐Schicht, die menschliche und mikrobielle Zellen umgibt, spielt eine wesentliche Rolle für die Fähigkeit des Immunsystems, Immuntoleranz und Gleichgewicht aufrechtzuerhalten sowie Krankheitserreger und Krebs zu bekämpfen. Endogene Anti‐Glykan‐Antikörper sind ein unverzichtbarer Bestandteil der Immunüberwachung, da sie abnormale mikrobielle Glykane, virale Glykoproteine und veränderte tumorassoziierte Kohlenhydratantigene identifizieren. Diese Glykane dienen wiederum als attraktive Ziele für passive und aktive Immunisierungsstrategien bei einer Reihe von Erkrankungen des Menschen. Das volle medizinische Potenzial der Glykane konnte bisher nicht voll ausgeschöpft werden, da sie eine enorme Komplexität und strukturelle Vielfalt aufweisen. Jüngste Fortschritte in der Glykansynthese, darunter automatisierte Glykansynthese, chemoenzymatische Strategien und Ein‐Topf‐Verfahren, ermöglichten einen beispiellosen Zugang zu genau definierten, homogenen Strukturen. Somit ebnen synthetische Glykane mit zunehmender struktureller Komplexität den Weg für eine Reihe von Anwendungen, von der Profilierung endogener Antikörperrepertoires zur Entdeckung von Biomarkern bis hin zur Entwicklung therapeutischer Antikörper und zum Impfstoffdesign. Hier fassen wir die Strategien zur Nutzung synthetischer Glykane für die Antikörperentwicklung und deren Anwendung in der Grundlagenforschung und der translationalen Medizin zusammen. Wir skizzieren, wie Anti‐Glykan‐Antikörper für diagnostische und therapeutische Zwecke eingesetzt werden, betonen dabei die Leistungsfähigkeit synthetischer Glykane und heben ihr Potenzial in der personalisierten Medizin hervor.

The dynamic glycan layer that surrounds human and microbial cells plays an essential role in the immune system's capacity to maintain immune tolerance and equilibrium, fight pathogens and cancer. Endogenous anti‐glycan antibodies are an indispensable part of immune surveillance, identifying abnormal microbial glycans, viral glycoproteins, and altered tumor‐associated carbohydrate antigens. These glycans serve in turn as attractive targets for passive and active immunization strategies in a range of human diseases. The enormous complexity and structural diversity of glycans has made it very difficult to unlock their full biomedical potential. Recent advances in glycan synthesis, including automated solid‐phase assembly, chemoenzymatic strategies, and one‐pot approaches, enabled unprecedented access to well‐defined, homogenous structures. Hence, synthetic glycans of increasing structural complexity pave the way for a range of applications, from profiling endogenous antibody repertoires for biomarker discovery to therapeutic antibody development and vaccine design. Here, we summarize the strategies to utilize synthetic glycans for antibody development and their application in basic research and translational medicine. We outline how anti‐glycan antibodies are utilized for diagnostic and therapeutic purposes, while emphasizing the power of synthetic glycans and highlighting their potential in personalized medicine.

Glycolipids play important roles in immune modulation, which makes them attractive components for vaccine delivery systems. However, access to these molecules remains a major limitation as most synthetic approaches rely on arduous solution-phase strategies. Here, we report a unified solid-phase platform that combines automated glycan assembly and iterative amide couplings for the rapid on-resin generation of a variety of mannan- and Gb3-derived glycolipids. This modular method enables the systematic diversification of glycan and lipid-anchor domains within a single synthetic framework. The synthetic constructs were used to generate glyco-functionalized liposomal nanoparticles with potential for immune cell targeting. Preliminary biological studies demonstrate efficient cell-associated uptake by antigen-presenting cells and show that biological performance is governed not only by glycan identity but also by anchor architecture.