Expert opinion on therapeutic targets
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Expert Opin. Ther. Targets · Aug 2005
ReviewThe ERK/MAPK pathway, as a target for the treatment of neuropathic pain.
Peripheral nerve injury produces neuropathic pain as well as phosphorylation of mitogen activated protein kinase (MAPK) family in dorsal root ganglia (DRG) and dorsal horn. Following nerve injury, phosphorylation of extracellular signal-regulated protein kinase (ERK), an important member of this family, is sequentially increased in neurons, microglia and astrocytes of the dorsal horn and gracile nucleus, and in injured large DRG neurons. ⋯ In several animal models of neuropathic pain, MEK inhibitors, known to suppress the synthesis of ERK, have proven effective to alleviate pain at various time points. Thus, the regulation of ERK/MAPK can be considered as a promising therapeutic target for the treatment of neuropathic pain.
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Expert Opin. Ther. Targets · Dec 2003
ReviewThe therapeutic potential of neuronal KCNQ channel modulators.
Neuronal KCNQ (Kv7) channels (KCNQ2-5 or Kv7.2-7.5, disclosed to date) were discovered by virtue of their homology with a known cardiac channel involved in long QT syndrome (KvLQT or KCNQ1, Kv7.1) and first disclosed in 1998. The involvement of KCNQ2 (Kv7.2) and KCNQ3 (Kv7.3) in a benign idiopathic neonatal epilepsy, KCNQ4 (Kv7.4) in a form of congenital deafness, and the discovery that neuronal KCNQ heteromultimers were among the molecular substrates of M-channels, resulted in a high level of interest for potential drug development strategies. ⋯ KCNQ blockers could likewise have utility in disorders characterised by neuronal hypoactivity, including cognition enhancement and perhaps disorders of mood. Emerging patent literature suggests significant interest in neuronal KCNQ modulation in the pharmaceutical industry and significant chemical diversity concerning KCNQ modulation.
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Expert Opin. Ther. Targets · Aug 2002
ReviewThe role of DC-SIGN and DC-SIGNR in HIV and Ebola virus infection: can potential therapeutics block virus transmission and dissemination?
Sexual transmission of HIV requires that the virus crosses mucosal barriers and disseminates into lymphoid tissue, the major site of viral replication. To achieve this, HIV might engage DC-SIGN, a calcium dependent lectin that is expressed on mucosal dendritic cells (DCs), which binds avidly to HIV. DC-SIGN and other attachment factors are likely to account for the well-known ability of DCs to enhance infection of T cells by HIV. ⋯ DC-SIGN and a related molecule, termed DC-SIGNR, also enhance infection by Ebola virus. The expression of these lectins on early targets of Ebola virus infection, like liver endothelial cells and alveolar macrophages, suggests an important role for DC-SIGN and DC-SIGNR in the establishment of Ebola infection. This article reviews the interaction of DC-SIGN and DC-SIGNR with HIV and Ebola, discusses the mechanism of DC-SIGN-mediated viral transmission and examines how this process could be inhibited by potential therapeutics.
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Expert Opin. Ther. Targets · Aug 2002
ReviewAirway smooth muscle: new targets for asthma pharmacotherapy.
Asthma, a chronic disease increasing in prevalence worldwide, is characterised by reversible airway obstruction, airway inflammation and airway smooth muscle (ASM) cell hyperplasia. The traditional view of ASM in asthma, as a regulator of bronchomotor tone, is rapidly changing. ⋯ This review discusses the synthetic function of ASM cells, defined as the ability to secrete cytokines, chemokines and growth factors and express surface receptors that are important for cell adhesion and leukocyte activation. Finally, the efficacy of established asthma therapies in modifying the synthetic function of ASM cells are compared and novel targets for pharmacological intervention are discussed.
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Expert Opin. Ther. Targets · Jun 2002
ReviewPeripheral metabotropic glutamate receptors as drug targets for pain relief.
The relatively new family of G-protein-coupled metabotropic glutamate receptors (mGluRs) is comprised of eight cloned subtypes, which are classified into three groups based on their sequence homology, signal transduction mechanisms and receptor pharmacology. It is now well-established that mGluRs in the central nervous system are essential for neuroplasticity associated with normal brain functions but are also critically involved in various neurological and psychiatric disorders. ⋯ Once the cellular effects of peripheral mGluR activation and inhibition are better understood, certain peripheral mGluR subtypes may become important novel therapeutic targets for the relief of pain associated with peripheral tissue injury. Peripherally acting drugs that modulate nociceptive processing through mGluRs should have the advantage of lacking the central side effects commonly observed with drugs interfering with glutamatergic transmission in the central nervous system.