Petra Ménová

A series of aryl α- l -fucosides was stereoselectively synthesized and tested for DC-SIGN binding. All compounds bound to the canonical binding site, while the most potent ligand ( K _D = 600 ± 130 μM; IC ₅₀ = 730 μM) also interacted with a secondary site.

Fluorescence detection of DNA and RNA G‐quadruplexes (G4s) is a very efficient strategy to assess not only the existence and prevalence of cellular G4s but also their relevance as targets for therapeutic interventions. Among the fluorophores used to this end, turn‐on probes are the most interesting since their fluorescence is triggered only upon interaction with their G4 targets, which ensures a high sensitivity and selectivity of detection. We reported on a series of twice‐as‐smart G4 probes, which are both smart G4 ligands (whose structure is reorganized upon interaction with G4s) and smart fluorescent probes (whose fluorescence is turned on upon interaction with G4s). The fine mechanistic details behind the excellent properties of the best prototype N‐TASQ remain to be deciphered: to investigate this, we report here on the synthesis and studies of two analogues, ^TzN‐TASQ and ^AlkN‐TASQ, and on a careful analysis of their G4‐interacting properties, investigated both in vitro and in silico. Our results show that fine‐tuning their constitutive structural elements allows for increasing the efficiency of both their ‘off’ (i. e., a conformation with a low fluorescence) and ‘on’ states (i. e., a conformation with a high fluorescence), which opens interesting ways for the design of more efficient fluorogenic G4 probes.

The asialoglycoprotein receptor (ASGPR) plays a crucial role in delivering therapeutics to hepatocytes. From nucleic acids to LYTACs and drugs, we explore the current state-of-the-art strategies for hepatocyte targeting via ASGPR.

Carbohydrates are essential mediators of many processes in health and disease. They regulate self-/non-self- discrimination, are key elements of cellular communication, cancer, infection and inflammation, and determine protein folding, function and life-times. Moreover, they are integral to the cellular envelope for microorganisms and participate in biofilm formation. These diverse functions of carbohydrates are mediated by carbohydrate-binding proteins, lectins, and the more the knowledge about the biology of these proteins is advancing, the more interfering with carbohydrate recognition becomes a viable option for the development of novel therapeutics. In this respect, small molecules mimicking this recognition process become more and more available either as tools for fostering our basic understanding of glycobiology or as therapeutics. In this review, we outline the general design principles of glycomimetic inhibitors (Section 2). This section is then followed by highlighting three approaches to interfere with lectin function, i.e. with carbohydrate-derived glycomimetics (Section 3.1), novel glycomimetic scaffolds (Section 3.2) and allosteric modulators (Section 3.3). We summarize recent advances in design and application of glycomimetics for various classes of lectins of mammalian, viral and bacterial origin. Besides highlighting design principles in general, we showcase defined cases in which glycomimetics have been advanced to clinical trials or marketed. Additionally, emerging applications of glycomimetics for targeted protein degradation and targeted delivery purposes are reviewed in Section 4.

DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin) is a pattern recognition receptor expressed on immune cells and involved in the recognition of carbohydrate signatures present on various pathogens, including HIV, Ebola, and SARS-CoV-2. Therefore, developing inhibitors blocking the carbohydrate-binding site of DC-SIGN could generate a valuable tool to investigate the role of this receptor in several infectious diseases. Herein, we performed a fragment-based ligand design using 4-quinolone as a scaffold. We synthesized a library of 61 compounds, performed a screening against DC-SIGN using an STD reporter assay, and validated these data using protein-based ¹H-¹⁵N HSQC NMR. Based on the structure-activity relationship data, we demonstrate that ethoxycarbonyl or dimethylaminocarbonyl in position 2 or 3 is favorable for the DC-SIGN binding activity, especially in combination with fluorine, ethoxycarbonyl, or dimethylaminocarbonyl in position 7 or 8. Furthermore, we demonstrate that these quinolones can allosterically modulate the carbohydrate binding site, which offers an alternative approach toward this challenging protein target.

Streptococcus pneumoniae causes life‐threatening diseases including meningitis, pneumonia and sepsis. Existing glycoconjugate vaccines based on purified capsular polysaccharides are widely used and help to prevent millions of deaths every year. Herein, the total syntheses of oligosaccharides resembling portions of the S. pneumoniae serotype 7F (ST7F) capsular polysaccharide repeating unit are reported. To define minimal glycan epitopes, glycan microarrays containing the synthetic oligosaccharides were used to screen human reference serum and revealed that both side chains of the ST7F play a key role in antigen recognition. The identification of protective minimal epitopes is vital to design efficient semi‐ and fully‐synthetic glycoconjugate vaccines.

GFP-like 3,5-difluoro-4-hydroxybenzylideneimidazolinone (FBI) and 3,5-bis(methoxy)-4-hydroxy-benzylideneimidazolinone (MBI) labels were attached to dCTP through a propargyl linker, and the resulting labeled nucleotides (dC^MBITP and dC^FBITP) were used for a facile enzymatic synthesis of oligonucleotide or DNA probes by polymerase-catalyzed primer extension. The MBI/FBI-labeled DNA probes exerted low fluorescence that was increased 2–3.2 times upon binding of a protein. The concept was demonstrated on sequence-specific binding of p53 to dsDNA and on nonspecific binding of single strand binding protein to an oligonucleotide. The FBI label was also used for a time-resolved experiment monitoring a single-nucleotide incorporation followed by primer extension by Vent(exo-) polymerase.