A Heparan Sulfate Mimetic RAFT Copolymer Inhibits SARS-CoV-2 Infection and Ameliorates Viral-Induced Inflammation.

The high transmissibility and mutation ability of coronaviruses enable them to easily escape existing immune protection and also pose a challenge to existing antiviral drugs. Moreover, drugs only targeting viruses cannot always attenuate the "cytokine storm". Herein, a synthetic heparan sulfate (HS) mimetic, HMSA-06 is reported, that exhibited antiviral activities against both the SARS-CoV-2 prototype and Omicron strains by targeting viral entry and replication.

Synthetic Access to l-Guluronic Acid via Fluorine-Directed C-5 Epimerization.

l-Guluronic acid is integral to the structures of alginates and to the pathogenesis of . The exploitation of this hexose in both existing and new contexts is, however, limited by its prohibitively high commercial cost. We report on a short and efficient synthetic route to an l-GulA building block from a simple d-mannose thioglycoside.

Synthesis of a deuterated disaccharide internal standard for LC-MS/MS quantitation of heparan sulfate in biological samples.

High levels of heparan sulfate (HS) are a marker for several mucopolysaccharidosis (MPS) disorders which are lysosomal storage diseases caused by genetic defects in HS-degrading enzymes. Quantitation of HS in biological samples is therefore critical for diagnosis and evaluating the efficacy of new therapies. Herein we present the efficient synthesis of a butylated GlcN-GlcA disaccharide and its deuterated derivative for use as an internal standard in a quantitative mass spectrometry-based assay for analysis of HS following butanolysis.

Sulfated Alginate for Biomedical Applications.

Alginate (Alg) polymers have received much attention due to the mild conditions required for gel formation and their good bio-acceptability. However, due to limited interactions with cells, many drugs, and biomolecules, chemically modified alginates are of great interest. Sulfated alginate (S-Alg) is a promising heparin-mimetic that continues to be investigated both as a drug molecule and as a component of biomaterials.

Amphiphilic Heparinoids as Potent Antiviral Agents against SARS-CoV-2.

Herein, we report the synthesis and biological evaluation of a novel series of heparinoid amphiphiles as inhibitors of heparanase and SARS-CoV-2. By employing a tailor-made synthetic strategy, a library of highly sulfated homo-oligosaccharides bearing d-glucose or a C5-epimer (i.e.

Origins of Temperature-Dependent Anomeric Selectivity in Glycosylations with an L-Idose Thioglycoside.

L-Idose thioglycosides are useful glycosyl donors for the construction of glycosaminoglycan oligosaccharides. When activated with NIS and catalytic TMSOTf in the presence of methanol, the stereoselectivity of O-glycosylation displays an intriguing dependence on the reaction temperature, with an increased preference for formation of the α-glycoside at higher temperatures. Using a combination of vt-NMR spectroscopy and DFT calculations, we show how a simple mechanistic model, based on competing reactions of the iodinated thioglycoside, can explain the main features of the temperature dependence.

Site-Selective Photobromination of -Acetylated Carbohydrates in Benzotrifluoride.

Ferrier photobromination enables direct synthetic access to valuable 5--bromosugars but has limitations that restrict its broader use. The reaction is typically conducted in CCl heated at reflux with irradiation by broad spectrum, energy-inefficient heat lamps. Herein, we demonstrate that the reaction proceeds rapidly and efficiently with PhCF as a safe and environmentally benign alternative to CCl at mild temperatures (≤40 °C) inside a compact photoreactor fitted with purple light-emitting diodes (LEDs).

Identification of a Pentasaccharide Lead Compound with High Affinity to the SARS-CoV-2 Spike Protein via In Silico Screening.

The spike (S) protein on the surface of the SARS-CoV-2 virus is critical to mediate fusion with the host cell membrane through interaction with angiotensin-converting enzyme 2 (ACE2). Additionally, heparan sulfate (HS) on the host cell surface acts as an attachment factor to facilitate the binding of the S receptor binding domain (RBD) to the ACE2 receptor. Aiming at interfering with the HS-RBD interaction to protect against SARS-CoV-2 infection, we have established a pentasaccharide library composed of 14,112 compounds covering the possible sulfate substitutions on the three sugar units (GlcA, IdoA, and GlcN) of HS.

Synthesis of sulfated alginate from its tributylammonium salt: Comparing the sulfating agents HSO-DCC and SO·py.

Direct comparison of the sulfating agents HSO-DCC and SO·py for the synthesis of sulfated alginate (S-Alg) as well as detailed characterisation of the products that form is lacking. This study involving three researchers used the tributylammonium salt of alginate (T-Alg) as a common substrate for the sulfation reactions. It was found that the use of HSO-DCC resulted in poor control of the degree of sulfation (DS) and that the S-Alg polymers contained nitrogen (determined by elemental analysis) as a result of formation of an unwanted N-acylurea adduct.

EUSEDcollab: a network of data from European catchments to monitor net soil erosion by water.

As a network of researchers we release an open-access database (EUSEDcollab) of water discharge and suspended sediment yield time series records collected in small to medium sized catchments in Europe. EUSEDcollab is compiled to overcome the scarcity of open-access data at relevant spatial scales for studies on runoff, soil loss by water erosion and sediment delivery. Multi-source measurement data from numerous researchers and institutions were harmonised into a common time series and metadata structure.

Siderophore conjugates to combat antibiotic-resistant bacteria.

Antimicrobial resistance (AMR) is a global threat to society due to the increasing emergence of multi-drug resistant bacteria that are not susceptible to our last line of defence antibiotics. Exacerbating this issue is a severe gap in antibiotic development, with no new clinically relevant classes of antibiotics developed in the last two decades. The combination of the rapidly increasing emergence of resistance and scarcity of new antibiotics in the clinical pipeline means there is an urgent need for new efficacious treatment strategies.

An Enzymatic Activity Assay for Heparanase That Is Useful for Evaluating Clinically Relevant Inhibitors and Studying Kinetics.

The enzyme heparanase cleaves heparan sulfate and is involved in a range of human diseases including cancer, inflammation, diabetes, and viral infection. There is a need for a simple and reliable enzymatic assay to allow for the screening of compounds to find inhibitors of heparanase. We have developed an assay that uses the heparinoid fondaparinux as enzyme substrate and detects one of the products of catalysis, which contains a newly formed reducing terminus, with the tetrazolium salt WST-1.

Synthesis of Uronic Acid 1-Azasugars as Putative Inhibitors of α-Iduronidase, β-Glucuronidase and Heparanase.

1-Azasugar analogues of l-iduronic acid (l-IdoA) and d-glucuronic acid (d-GlcA) and their corresponding enantiomers have been synthesized as potential pharmacological chaperones for mucopolysaccharidosis I (MPS I), a lysosomal storage disease caused by mutations in the gene encoding α-iduronidase (IDUA). The compounds were efficiently synthesized in nine or ten steps from d- or l-arabinose, and the structures were confirmed by X-ray crystallographic analysis of key intermediates. All compounds were inactive against IDUA, although l-IdoA-configured 8 moderately inhibited β-glucuronidase (β-GLU).

An Improved Protocol for the Stereoselective Synthesis of β-d-Glycosyl Fluorides from 2--Acyl Thioglycosides.

A safe and operationally simple protocol for the preparation of β-d-glycosyl fluorides is presented. We demonstrate that a precise combination of XtalFluor-M, -bromosuccinimide, and EtN·3HF can mediate facile, high-yielding, and diastereoselective conversions of 2--acyl thioglycosides to β-d- and other 1,2- glycosyl fluorides. The key roles of these reagents are dissected in this work, as is the impact of their interplay on the fluorination stereoselectivity.

Evidence for Multiple Binding Modes in the Initial Contact Between SARS-CoV-2 Spike S1 Protein and Cell Surface Glycans.

Infection of host cells by SARS-CoV-2 begins with recognition by the virus S (spike) protein of cell surface heparan sulfate (HS), tethering the virus to the extracellular matrix environment, and causing the subunit S1-RBD to undergo a conformational change into the 'open' conformation. These two events promote the binding of S1-RBD to the angiotensin converting enzyme 2 (ACE2) receptor, a preliminary step toward viral-cell membrane fusion. Combining ligand-based NMR spectroscopy with molecular dynamics, oligosaccharide analogues were used to explore the interactions between S1-RBD of SARS CoV-2 and HS, revealing several low-specificity binding modes and previously unidentified potential sites for the binding of extended HS polysaccharide chains.

SARS-CoV-2 triggers complement activation through interactions with heparan sulfate.

Objectives: To determine whether SARS-CoV-2 can trigger complement activation, the pathways that are involved and the functional significance of the resultant effect.

Methods: SARS-CoV-2 was inoculated into a human lepirudin-anticoagulated whole blood model, which contains a full repertoire of complement factors and leukocytes that express complement receptors. Complement activation was determined by measuring C5a production with an ELISA, and pretreatment with specific inhibitors was used to identify the pathways involved.

Structural Insights into Pixatimod (PG545) Inhibition of Heparanase, a Key Enzyme in Cancer and Viral Infections.

Pixatimod (PG545), a heparan sulfate (HS) mimetic and anticancer agent currently in clinical trials, is a potent inhibitor of heparanase. Heparanase is an endo-β-glucuronidase that degrades HS in the extracellular matrix and basement membranes and is implicated in numerous pathological processes such as cancer and viral infections, including SARS-CoV-2. To understand how PG545 interacts with heparanase, we firstly carried out a conformational analysis through a combination of NMR experiments and molecular modelling which showed that the reducing end β-D-glucose residue of PG545 adopts a distorted conformation.

Development of Improved Synthetic Routes to Pixatimod (PG545), a Sulfated Oligosaccharide-Steroid Conjugate.

The heparan sulfate (HS) mimetic pixatimod (PG545) is a highly potent inhibitor of angiogenesis, tumor growth, and metastasis currently in clinical trials for cancer. PG545 has also demonstrated potent antiviral activity against numerous HS-dependent viruses, including SARS-CoV-2, and shows promise as an antiviral drug for the treatment of COVID-19. Structurally, PG545 consists of a fully sulfated tetrasaccharide conjugated to the steroid 5α-cholestan-3β-ol.

From Cancer to COVID-19: A Perspective on Targeting Heparan Sulfate-Protein Interactions.

Heparan sulfate (HS) is a complex, polyanionic polysaccharide ubiquitously expressed on cell surfaces and in the extracellular matrix. HS interacts with numerous proteins to mediate a vast array of biological and pathological processes. Inhibition of HS-protein interactions is thus an attractive approach for new therapeutic development for cancer and infectious diseases, including COVID-19; however, synthesis of well-defined native HS oligosaccharides remains challenging.

Evidence of a putative glycosaminoglycan binding site on the glycosylated SARS-CoV-2 spike protein N-terminal domain.

SARS-CoV-2 has rapidly spread throughout the world's population since its initial discovery in 2019. The virus infects cells via a glycosylated spike protein located on its surface. The protein primarily binds to the angiotensin-converting enzyme-2 (ACE2) receptor, using glycosaminoglycans (GAGs) as co-receptors.

Corrigendum: Heparanase Promotes Syndecan-1 Expression to Mediate Fibrillar Collagen and Mammographic Density in Human Breast Tissue Cultured .

[This corrects the article DOI: 10.3389/fcell.2020.