Inhibition of inflammation by a p38 MAP kinase targeted cell permeable peptide.
p38 MAPK has been the key therapeutic target for multiple inflammation diseases. However, the clinical applications of p38 inhibitors, most of which target on the ATP binding groove in the kinase, have been held back, largely because of their limited specificity and severe side-effects. An alternative strategy to generate highly selective p38 inhibitor is to block the specific interaction in the p38 signal pathway. Based on the hypothesis that specific binding peptides targeting on the docking groove would interfere the intrinsic interaction between p38 and its partners, we have designed a fusion peptide containing 12aa p38 docking sequence derived from MKK3b and 11aa HIV-TAT transmembrane sequence to form a cell permeable peptide. The peptide specifically binds to p38, and aborts its interaction with upstream kinase as well as downstream substrates, and thus to inhibit p38 phosphorylation and its signaling. Furthermore, the induction and secretion of TNFalpha and other inflammatory factors by LPS are blocked in peptide treated cells and mice. Finally the peptide has been shown to significantly inhibit ear oedema in mice. Therefore, the peptide holds great potential as an anti-inflammation agent for the treatment of inflammation and its related diseases.
Fu
Jing
J
National Laboratory of Protein Engineering and Plant Genetic Engineering, College of Life Sciences, Peking University, Beijing 100871, People's Republic of China.
Meng
Xianmei
X
He
Junyun
J
Gu
Jun
J
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology*; D002351:Carrageenan; D002463:Cell Membrane Permeability / Q000187:drug effects; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D015696:Gene Products, tat / Q000138:chemical synthesis / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D048371:MAP Kinase Kinase 3 / Q000138:chemical synthesis / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000138:chemical synthesis / Q000494:pharmacology; D020349:Surface Plasmon Resonance; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D015696:Gene Products, tat; D008070:Lipopolysaccharides; D010455:Peptides; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D002351:Carrageenan; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; C482530:MAP2K3 protein, human