ABSTRACT
New structural classes of K(V)1.3 and IK-1 ion channel blockers have been identified based on a virtual high throughput screening approach using a homology model of KcsA. These compounds display inhibitory effects on T-cell and/or keratinocyte proliferation and immunosuppressant activity within a DTH animal model.
Subject(s)
Immunosuppressive Agents/chemical synthesis , Immunosuppressive Agents/pharmacology , Intermediate-Conductance Calcium-Activated Potassium Channels/antagonists & inhibitors , Kv1.3 Potassium Channel/antagonists & inhibitors , Potassium Channel Blockers/chemical synthesis , Potassium Channel Blockers/pharmacology , Animals , Calcium Signaling/drug effects , Calcium Signaling/physiology , Cell Proliferation/drug effects , Cells, Cultured , Disease Models, Animal , Humans , Hypersensitivity, Delayed/drug therapy , Hypersensitivity, Delayed/metabolism , Immunosuppressive Agents/classification , Intermediate-Conductance Calcium-Activated Potassium Channels/chemistry , Intermediate-Conductance Calcium-Activated Potassium Channels/physiology , Keratinocytes/drug effects , Keratinocytes/physiology , Kv1.3 Potassium Channel/chemistry , Kv1.3 Potassium Channel/physiology , Patch-Clamp Techniques , Potassium Channel Blockers/classificationABSTRACT
Human Vgamma9delta2 T lymphocytes are suggested to play an important role in the immune response to various microbial pathogens. In contrast to alphabeta T cells, gammadelta T lymphocytes recognize small, non-protein, phosphate-bearing antigens (phosphoantigens) in a major histocompatibility complex-independent manner. Four different phosphoantigens termed TUBag1 to TUBag4 with a common 3-formyl-1-butyl-pyrophosphate moiety and isopentenyl-pyrophosphate have been isolated and identified from mycobacteria. However, natural occurring gammadelta T cell ligands from other bacterial species were not characterized so far. Here, we describe the structural identification of the two compounds responsible for the gammadelta T cell-stimulating capacity of Escherichia coli as similar to the mycobacterial phosphoantigens 3-formyl-1-butyl-pyrophosphate and its M(r) 275 homologue TUBag2. In addition, E. coli phosphoantigens exert bioactivities on gammadelta T cells with similar potencies to the mycobacterial phosphoantigens at 5-15 nm concentration. Furthermore, our results clearly prove that the deoxyxylulose 5-phophate pathway (also referred to as Rohmer metabolic route of isoprenoid biosynthesis) is essential for the biosynthesis of the phosphoantigens in E. coli. Because this pathway is absent from human cells, it proves an ideal target for focusing efficiently the antimicrobial selectivity of human gammadelta T lymphocytes.
