Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD4 T-lymphocytes, which orchestrate immune responses, receive a cognitive signal when clonally distributed receptors are occupied by MHC class II bound peptides on antigen-presenting cells. The latter provide costimulatory or accessory signals through macromolecules such as B7.1 and B7.2 which interact with coreceptors on T-cells to regulate outcomes in terms of T-cell activation or specific non-responsiveness. Complementary studies at the chemical level have implicated Schiff base formation between specialised carbonyls and amines, constitutively expressed on antigen-presenting cell and T-cell surfaces, as an essential element in specific T-cell activation. The small xenobiotic Schiff base forming molecule tucaresol, which substitutes for the physiological donor of carbonyl groups to provide a costimulatory signal to CD4 T-helper lymphocytes (Th-cells), has been developed for testing as an immunopotentiatory drug. Tucaresol, which is orally bioavailable and systemically active, enhances CD4 Th-cell and CD8 cytotoxic T-cell responses in vivo and selectively favours a Th1-type profile of cytokine production. In murine models of virus infection and syngeneic tumour growth it has substantial therapeutic activity. Schiff base formation by tucaresol on T-cell surface amines provides a costimulatory signal to the T-cell through a mechanism that activates clofilium-sensitive K+ and Na+ transport. The signalling pathway utilised by tucaresol converges with T-cell receptor signalling at the level of MAP kinase, promoting the tyrosyl phosphorylation of ERK2 by MEK (mitogen-activated protein kinase kinase). The Schiff base forming class of immunopotentiatory drug provides the first orally active, mechanism-based immunopotentiatory agents for therapeutic testing. Tucaresol is currently undergoing pilot phase I/II clinical trials as an immunopotentiator in chronic hepatitis B virus infection, HIV infection and malignant melanoma.
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PMID:Schiff base forming drugs: mechanisms of immune potentiation and therapeutic potential. 889 54

Influenza A and B viruses are still a major worldwide threat. We demonstrate that influenza B virus infection induces signaling via the Raf/MEK/ERK cascade, a process required for efficient virus production. Expression of dominant-negative Raf and ERK mutants or treatment with a MEK inhibitor (U0126) strongly impaired viral propagation, while selective activation of the pathway resulted in increased virus titers. MEK inhibition appears to interfere with a distinct viral nuclear export process. Most importantly, no resistant virus variants emerged in the presence of U0126 demonstrating that influenza viruses cannot easily adapt to the missing cellular function.
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PMID:MEK inhibition impairs influenza B virus propagation without emergence of resistant variants. 1501 48

CD4+ T lymphocytes, which orchestrate immune responses, receive a cognitive signal when clonally distributed receptors are occupied by peptides bound to major histocompatibility complex (MHC) class II molecules on antigen-presenting cells. The latter cells provide costimulatory or accessory signals through macromolecules such as B7.1 and B7.2, which interact with coreceptors on T cells to regulate outcomes in terms of T cell activation or specific nonresponsiveness. Complementary studies of the interactions between antigen-presenting cells and T helper cells at the chemical level have implicated Schiff base formation between specialised carbonyls and amines, constitutively expressed on the surfaces of antigen-presenting cells and T cells, as an essential element in specific T cell activation. Small Schiff base-forming molecules can substitute for the natural donor of carbonyl groups and provide a costimulatory signal to the T cell. From this class of Schiff base-forming costimulatory molecules, the small xenobiotic substituted benzaldehyde, tucaresol, has been selected for development and testing as an immunopotentiatory drug. Tucaresol, which is orally bioavailable and systemically active, enhances CD4+ T helper cell and CD8+ cytotoxic T cell responses in vivo, and selectively favours a T helper 1 profile of cytokine production. In murine models of virus infection and syngeneic tumour growth it has substantial therapeutic activity. Schiff base formation by tucaresol on T cell surface amines provides a costimulatory signal to the T cell through a mechanism that activates clofilium-sensitive K(+) and Na(+) transport. The pathway utilised by tucaresol converges with T cell receptor signalling at the level of mitogen-activated protein (MAP) kinase, promoting the activation of MAP kinase kinase (MEK) and consequential tyrosyl phosphorylation of ERK2. Tucaresol is the first orally active, mechanism-based immunopotentiatory drug available for therapeutic testing. It is currently undergoing phase I/II clinical trials in chronic hepatitis B virus infection, HIV infection and malignant melanoma.
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PMID:[Not Available]. 1803 Oct 95