Sulfated polymannuroguluronate, a novel anti-acquired immune deficiency syndrome drug candidate, blocks neuroinflammatory signalling by targeting the transactivator of transcription (Tat) protein.
Impaired inflammatory functions may be critical factors in the mechanisms of severe CNS disorders classified as the human immunodeficiency virus-1 (HIV-1)-associated dementia (HAD). Evidence indicates that a viral gene product, the transactivator of transcription protein (Tat), can markedly contribute to these events. We herein report that sulfated polymannuroguluronate (SPMG), a novel anti-acquired immunodeficiency syndrome drug candidate now in a phase II clinical trial, significantly reversed Tat-induced release of pro-inflammatory cytokines [tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta) and IL-6] and dose dependently decreased the accumulation of reactive oxygen species and nitric oxide in THP-1 cells. Furthermore, SPMG potently arrested Tat-triggered protein kinase C (PKC)-dependent PKC-mu activation, and blocked the downstream extracellular-signal regulated kinase 1/2- and c-jun amino-terminal kinase-mediated signalling pathways. These molecular mechanisms could be attributed to the fact that SPMG preferentially bound to the basic domain (amino acids 47-57) of the Tat protein with high affinity (K(D) approximately 8.69 x 10(-10) m), leading to abrogation of Tat-mediated neuroinflammation and neurotoxicity. These data demonstrate that SPMG might serve as a valuable therapeutic intervention for Tat-induced profound pro-inflammatory effects in the brain, and subsequent pathologic events of HAD.
Hui
Bin
B
Department of Pharmacology, Marine Drug and Food Institute, Ocean University of China, Qingdao.
Xia
Wei
W
Li
Jing
J
Wang
Limei
L
Ai
Jing
J
Geng
Meiyu
M
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy; D001665:Binding Sites / Q000187:drug effects; D015153:Blotting, Western / Q000379:methods; D002460:Cell Line; D003198:Computer Simulation; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015696:Gene Products, tat / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000139:chemically induced* / Q000188:drug therapy*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008954:Models, Biological; D009000:Monocytes; D009569:Nitric Oxide / Q000378:metabolism; D011134:Polysaccharides / Q000494:pharmacology* / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors; D054322:tat Gene Products, Human Immunodeficiency Virus
D016207:Cytokines; D015696:Gene Products, tat; D011134:Polysaccharides; D017382:Reactive Oxygen Species; C489185:sulfated polymannuroguluronate; D054322:tat Gene Products, Human Immunodeficiency Virus; D009569:Nitric Oxide; D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4