ABSTRACT
Severe influenza A virus (IAV) infections can result in hyper-inflammation, lung injury and acute respiratory distress syndrome1-5 (ARDS), for which there are no effective pharmacological therapies. Necroptosis is an attractive entry point for therapeutic intervention in ARDS and related inflammatory conditions because it drives pathogenic lung inflammation and lethality during severe IAV infection6-8 and can potentially be targeted by receptor interacting protein kinase 3 (RIPK3) inhibitors. Here we show that a newly developed RIPK3 inhibitor, UH15-38, potently and selectively blocked IAV-triggered necroptosis in alveolar epithelial cells in vivo. UH15-38 ameliorated lung inflammation and prevented mortality following infection with laboratory-adapted and pandemic strains of IAV, without compromising antiviral adaptive immune responses or impeding viral clearance. UH15-38 displayed robust therapeutic efficacy even when administered late in the course of infection, suggesting that RIPK3 blockade may provide clinical benefit in patients with IAV-driven ARDS and other hyper-inflammatory pathologies.
Subject(s)
Lung Injury , Necroptosis , Orthomyxoviridae Infections , Protein Kinase Inhibitors , Receptor-Interacting Protein Serine-Threonine Kinases , Animals , Female , Humans , Male , Mice , Alveolar Epithelial Cells/pathology , Alveolar Epithelial Cells/drug effects , Alveolar Epithelial Cells/virology , Alveolar Epithelial Cells/metabolism , Influenza A virus/classification , Influenza A virus/drug effects , Influenza A virus/immunology , Influenza A virus/pathogenicity , Lung Injury/complications , Lung Injury/pathology , Lung Injury/prevention & control , Lung Injury/virology , Mice, Inbred C57BL , Necroptosis/drug effects , Orthomyxoviridae Infections/complications , Orthomyxoviridae Infections/drug therapy , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/mortality , Orthomyxoviridae Infections/virology , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Receptor-Interacting Protein Serine-Threonine Kinases/metabolism , Receptor-Interacting Protein Serine-Threonine Kinases/antagonists & inhibitors , Respiratory Distress Syndrome/complications , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/prevention & control , Respiratory Distress Syndrome/virologyABSTRACT
Pd-catalysed annulation reactions between indole derivatives and internal alkyne esters leading to various pyrrolo[1,2-a]indoles and pyrroloquinolines have been developed. The strategy involves an intermolecular addition of the indole nitrogen on to the internal alkyne ester followed by an intramolecular insertion of a vinyl-palladium complex into the carbonyl group. This method offers a facile and practical approach to pyrrolo[1,2-a]indoles and pyrroloquinolines.
ABSTRACT
Cu(OTf)2 catalyzed [6 + 2] cycloaddition reaction of indolyl-2-carbinols with various dienophiles such as indole derived α,ß-unsaturated esters, ketones, nitriles and cinnamates is described. The strategy was further applied for the synthesis of optically active pyrrolo[1,2-a]indoles in >97% de using the chiral auxiliary based approach.
ABSTRACT
An efficient synthesis of dimethyl tripartin as a synthetic precursor of natural product tripartin, the first natural specific inhibitor of histone H3 lysine 9 demethylase KDM4, is described. The synthesis of dimethyl tripartin was achieved in a six-step longest linear sequence starting from commercially available 3,5-dimethoxy benzaldehyde with 21% overall yield, using ClTi(O i Pr)3-mediated dichloromethine insertion as the key step.
ABSTRACT
Lewis acid catalysed [6+2] cycloaddition reaction for the synthesis of pyrrolo[1,2-a]indoles generating three contiguous stereocenters in a highly regio- and diastereoselective manner has been developed and further applied for the construction of the fully functionalized tricyclic core of yuremamine.