ABSTRACT
Aberrant activation of caspase-6 (C6) in the absence of other hallmarks of apoptosis has been demonstrated in cells and tissues from patients with Huntington disease (HD) and animal models. C6 activity correlates with disease progression in patients with HD and the cleavage of mutant huntingtin (mHTT) protein is thought to strongly contribute to disease pathogenesis. Here we show that the mHTT1-586 fragment generated by C6 cleavage interacts with the zymogen form of the enzyme, stabilizing a conformation that contains an active site and is prone to full activation. This shift toward enhanced activity can be prevented by a small-molecule inhibitor that blocks the interaction between C6 and mHTT1-586. Molecular docking studies suggest that the inhibitor binds an allosteric site in the C6 zymogen. The interaction of mHTT1-586 with C6 may therefore promote a self-reinforcing, feedforward cycle of C6 zymogen activation and mHTT cleavage driving HD pathogenesis.
Subject(s)
Caspase 6/metabolism , Huntingtin Protein/genetics , Huntington Disease/metabolism , Allosteric Regulation/genetics , Animals , Apoptosis , COS Cells , Caspase 6/physiology , Chlorocebus aethiops , Huntingtin Protein/metabolism , Huntington Disease/pathology , Molecular Docking Simulation/methods , Nerve Tissue Proteins/metabolism , Neurons/metabolism , Nuclear Proteins/metabolismABSTRACT
A series of 3-hydroxybenzo[b]thiophene-2-carboxylic acid derivatives has been prepared and subsequently evaluated with regards to the inhibition of 5-LOX/COX. Structure optimization furnished derivatives with promising in vitro activity as dual 5-LOX/COX inhibitors with submicromolar IC(50) values for inhibition of 5-LOX and COX-1, respectively.
Subject(s)
Arachidonate 5-Lipoxygenase/chemistry , Cyclooxygenase 1/chemistry , Cyclooxygenase Inhibitors/chemical synthesis , Lipoxygenase Inhibitors/chemical synthesis , Thiophenes/chemistry , Arachidonate 5-Lipoxygenase/metabolism , Carboxylic Acids/chemical synthesis , Carboxylic Acids/chemistry , Carboxylic Acids/metabolism , Cyclooxygenase 1/metabolism , Cyclooxygenase Inhibitors/chemistry , Cyclooxygenase Inhibitors/metabolism , Lipoxygenase Inhibitors/chemistry , Lipoxygenase Inhibitors/metabolism , Protein Binding , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/metabolismABSTRACT
A series of previously unreported α-hydroxy hydrazonates were synthesized and tested for their antimalarial properties. Structure optimization of the antiplasmodially active α-hydroxy hydrazonate III furnished derivatives with strong in-vitro antimalarial activity against 3D7 strains of Plasmodium falciparum with IC(50) values lower than 2.0 µM.