Novel Macrocyclic NLRP3 Inhibitors.

Aberrant activation of NLRP3 due to persistent tissue damage, misfolded proteins or crystal deposits has been linked to multiple chronic inflammatory disorders such as cryopyrin-associated periodic syndrome (CAPS), neurodegenerative diseases, gouty arthritis, and numerous others. Hence, there has been an increasing interest in NLRP3 inhibitors as therapeutics. A first generation of NLRP3 inhibitors bearing a sulfonylurea core such as MCC950 (developed by Pfizer) were discovered by phenotypic screening, however their mode of action was only elucidated later.

Enhancing Drug Discovery and Development through the Integration of Medicinal Chemistry, Chemical Biology, and Academia-Industry Partnerships: Insights from Roche's Endocannabinoid System Projects.

The endocannabinoid system (ECS) is a critical regulatory network composed of endogenous cannabinoids (eCBs), their synthesizing and degrading enzymes, and associated receptors. It is integral to maintaining homeostasis and orchestrating key functions within the central nervous and immune systems. Given its therapeutic significance, we have launched a series of drug discovery endeavors aimed at ECS targets, including peroxisome proliferator-activated receptors (PPARs), cannabinoid receptors types 1 (CB1R) and 2 (CB2R), and monoacylglycerol lipase (MAGL), addressing a wide array of medical needs.

Liver-Targeted Anti-HBV Single-Stranded Oligonucleotides with Locked Nucleic Acid Potently Reduce HBV Gene Expression In Vivo.

Chronic hepatitis B infection (CHB) is an area of high unmet medical need. Current standard-of-care therapies only rarely lead to a functional cure, defined as durable hepatitis B surface antigen (HBsAg) loss following treatment. The goal for next generation CHB therapies is to achieve a higher rate of functional cure with finite treatment duration.

Hepatitis C virus infection propagates through interactions between Syndecan-1 and CD81 and impacts the hepatocyte glycocalyx.

The hepatitis C virus (HCV) infects hepatocytes after binding to heparan sulfate proteoglycans, in particular Syndecan-1, followed by recognition of the tetraspanin CD81 and other receptors. Heparan sulfate proteoglycans are found in a specific microenvironment coating the hepatocyte surface called the glycocalyx and are receptors for extracellular matrix proteins, cytokines, growth factors, lipoproteins, and infectious agents. We investigated the mutual influence of HCV infection on the glycocalyx and revealed new links between Syndecan-1 and CD81.

Far-Red Fluorescent Lipid-Polymer Probes for an Efficient Labeling of Enveloped Viruses.

Far-red emitting fluorescent lipid probes are desirable to label enveloped viruses, for their efficient tracking by optical microscopy inside autofluorescent cells. Most used probes are rapidly released from membranes, leading to fluorescence signal decay and loss of contrast. Here, water-soluble lipid-polymer probes are synthesized harboring hydrophilic or hydrophobic far-red emitting dyes, and exhibiting enhanced brightness.

Arbidol as a broad-spectrum antiviral: an update.

Arbidol (ARB) is a Russian-made small indole-derivative molecule, licensed in Russia and China for prophylaxis and treatment of influenza and other respiratory viral infections. It also demonstrates inhibitory activity against other viruses, enveloped or not, responsible for emerging or globally prevalent infectious diseases such as hepatitis B and C, gastroenteritis, hemorrhagic fevers or encephalitis. In this review, we will explore the possibility and pertinence of ARB as a broad-spectrum antiviral, after a careful examination of its physico-chemical properties, pharmacokinetics, toxicity, and molecular mechanisms of action.

Arbidol inhibits viral entry by interfering with clathrin-dependent trafficking.

Arbidol (ARB) is a broad-spectrum antiviral displaying activity against a number of enveloped and non-enveloped viruses. It was described as a viral entry inhibitor and shown to interact at the molecular level with lipid membranes and viral fusion glycoproteins to impede viral entry and fusion. However its mechanism of action at the cellular level remains unknown.

Silibinin inhibits hepatitis C virus entry into hepatocytes by hindering clathrin-dependent trafficking.

Hepatitis C virus (HCV) is a global health concern infecting 170 million people worldwide. Previous studies indicate that the extract from milk thistle known as silymarin and its main component silibinin inhibit HCV infection. Here we investigated the mechanism of anti-HCV action of silymarin-derived compounds at the molecular level.

Lipids: a key for hepatitis C virus entry and a potential target for antiviral strategies.

Viruses have evolved to complex relationship with their host cells. Many viruses modulate the lipid composition, lipid synthesis and signaling of their host cell. Lipids are also an essential part of the life cycle of the hepatitis C virus (HCV).