Evolution of SARS-CoV-2 spike trimers towards optimized heparan sulfate cross-linking and inter-chain mobility.

The heparan sulfate (HS)-rich extracellular matrix (ECM) serves as an initial interaction site for the homotrimeric spike (S) protein of SARS-CoV-2 to facilitate subsequent docking to angiotensin-converting enzyme 2 (ACE2) receptors and cellular infection. More recent variants, notably Omicron, have evolved by swapping several amino acids to positively charged residues to enhance the interaction of the S-protein trimer with the negatively charged HS. However, these enhanced interactions may reduce Omicron's ability to move through the HS-rich ECM to effectively find ACE2 receptors and infect cells, raising the question of how to mechanistically explain HS-associated viral movement.

Chemical and biological differences between original and mimetic pentosan polysulfates.

Pentosan polysulfate sodium (PPS) is a semi-synthetic, heparin-like polysaccharide with manifold therapeutic actions. It is approved for treatment of bladder pain syndrome / interstitial cystitis in humans and treatment of musculoskeletal diseases in animals. PPS is produced by a complex procedure using beech wood as starting material.

Pentosan Polysulfate Inhibits Attachment and Infection by SARS-CoV-2 In Vitro: Insights into Structural Requirements for Binding.

Two years since the outbreak of the novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic, there remain few clinically effective drugs to complement vaccines. One is the anticoagulant, heparin, which in 2004 was found able to inhibit invasion of SARS-CoV (CoV-1) and which has been employed during the current pandemic to prevent thromboembolic complications and moderate potentially damaging inflammation. Heparin has also been shown experimentally to inhibit SARS-CoV-2 attachment and infection in susceptible cells.

Computer-Aided Design and Synthesis of a New Class of PEX14 Inhibitors: Substituted 2,3,4,5-Tetrahydrobenzo[F][1,4]oxazepines as Potential New Trypanocidal Agents.

African and American trypanosomiases are estimated to affect several million people across the world, with effective treatments distinctly lacking. New, ideally oral, treatments with higher efficacy against these diseases are desperately needed. Peroxisomal import matrix (PEX) proteins represent a very interesting target for structure- and ligand-based drug design.

Structure-Activity Relationship in Pyrazolo[4,3-]pyridines, First Inhibitors of PEX14-PEX5 Protein-Protein Interaction with Trypanocidal Activity.

protists are pathogens leading to a spectrum of devastating infectious diseases. The range of available chemotherapeutics against is limited, and the existing therapies are partially ineffective and cause serious adverse effects. Formation of the PEX14-PEX5 complex is essential for protein import into the parasites' glycosomes.

Celastrol Promotes Weight Loss in Diet-Induced Obesity by Inhibiting the Protein Tyrosine Phosphatases PTP1B and TCPTP in the Hypothalamus.

Celastrol is a natural pentacyclic triterpene used in traditional Chinese medicine with significant weight-lowering effects. Celastrol-administered mice at 100 μg/kg decrease food consumption and body weight via a leptin-dependent mechanism, yet its molecular targets in this pathway remain elusive. Here, we demonstrate in vivo that celastrol-induced weight loss is largely mediated by the inhibition of leptin negative regulators protein tyrosine phosphatase (PTP) 1B (PTP1B) and T-cell PTP (TCPTP) in the arcuate nucleus (ARC) of the hypothalamus.

Enantioselective Visible-Light-Induced Radical-Addition Reactions to 3-Alkylidene Indolin-2-ones.

The title compounds underwent a facile and high-yielding addition reaction (19 examples, 66-99% yield) with various N-(trimethylsilyl)methyl-substituted amines upon irradiation with visible light and catalysis by a metal complex. If the alkylidene substituent is non-symmetric and if the reaction is performed in the presence of a chiral hydrogen-bonding template, products are obtained with significant enantioselectivity (58-72% ee) as a mixture of diastereoisomers. Mechanistic studies suggest a closed catalytic cycle for the photoactive metal complex.

Enantioselective catalysis of photochemical reactions.

The nature of the excited state renders the development of chiral catalysts for enantioselective photochemical reactions a considerable challenge. The absorption of a 400 nm photon corresponds to an energy uptake of approximately 300 kJ mol(-1) . Given the large distance to the ground state, innovative concepts are required to open reaction pathways that selectively lead to a single enantiomer of the desired product.

Visible-light-induced, Ir-catalyzed reactions of N-methyl-N-((trimethylsilyl)methyl)aniline with cyclic α,β-unsaturated carbonyl compounds.

N-Methyl-N-((trimethylsilyl)methyl)aniline was employed as reagent in visible-light-induced, iridium-catalyzed addition reactions to cyclic α,β-unsaturated carbonyl compounds. Typical reaction conditions included the use of one equivalent of the reaction substrate, 1.5 equivalents of the aniline and 2.