Peptides based on the transmembrane domain of a toll-like receptor (tlr) for treatment of tlr-mediated diseases

Abstract

Peptides are provided that are capable of inhibiting cell activation mediated by a Toll-like receptor (TLR) selected from TLR 1, 2, 4 or 6, said peptide comprising a sequence consisting of, or found within, the sequence of the transmembrane domain of a TLR selected from TLR 1, 2, 4 or 6 and optionally cytoplasmic and extracellular regions flanking the transmembrane domain. These peptides as well as pharmaceutical composition comprising them are useful for the treatment of TLR-mediated disease.

What is claimed is: 
     
         1 . A synthetic peptide comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 41-74, said amino acid sequence being linked at its N- and/or C-termini to an additional one to four positively charged amino acid residues, wherein said synthetic peptide inhibits cell activation mediated by a TLR. 
     
     
         2 . The synthetic peptide according to  claim 1 , wherein said peptide comprises at most 30 amino acid residues. 
     
     
         3 . The synthetic peptide according to  claim 1 , wherein said positively charged amino acid is selected from the group consisting of lysine, arginine, histidine and ornithine. 
     
     
         4 . The synthetic peptide according to  claim 3 , wherein one or two lysine residues are added to one or both of the N or C termini. 
     
     
         5 . The synthetic peptide according to  claim 1 , wherein said amino acid sequence comprises at least one D amino acid. 
     
     
         6 . A pharmaceutical composition comprising the synthetic peptide according to  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         7 . A method for the treatment of a TLR-mediated disease, the method comprising administering to a patient suffering from said TLR-mediated disease an effective amount of a synthetic peptide comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 1-121. 
     
     
         8 . The method according to  claim 7 , wherein said TLR-mediated disease is an inflammation or cancer. 
     
     
         9 . The method according to  claim 8 , wherein said inflammation is acute inflammation. 
     
     
         10 . The method according to  claim 8 , wherein said cancer is selected from the group consisting of prostate cancer, gastric carcinoma, colon cancer, hepatocellular carcinoma, epithelial ovarian cancer, cervical squamous cell carcinomas, breast cancer, lung cancer, melanoma and neuroblastoma. 
     
     
         11 . The method according to  claim 7 , wherein said TLR-mediated disease is selected from the group consisting of a septic shock, a systemic inflammatory response syndrome (SIRS), an acute inflammation, a post ischemic reperfusion injury, an inflammatory bowel disease, an exacerbation of latent or active infection, a congestive heart failure, an autoimmune disease, a chronic obstructive pulmonary disease, a predisposition to pulmonary bacterial infection, a congestive heart failure with pulmonary edema, a rheumatoid disease, a degenerative disease, a neurodegenerative disease, a fibrotic disease, a cachexia, a graft rejection, a radiation damage, an asthma and a cancer.