Methods and pharmaceutical compositions for the treatment of respiratory tract infections

Abstract

The present invention relates to methods and pharmaceutical compositions for the treatment of respiratory tract infections. More particularly, the present invention relates to a TLR5 agonist for use in a method for treating a respiratory tract infection.

1 - 20 . (canceled) 
     
     
         21 . A pharmaceutical composition for treating a respiratory tract infection, said pharmaceutical composition comprising a TLR5 agonist. 
     
     
         22 . The pharmaceutical composition according to  claim 21  which is formulated to be compatible with a topical administration. 
     
     
         23 . The pharmaceutical composition according to  claim 22  which is formulated in an aerosol form, a spray, a mist or in the form of drops. 
     
     
         24 . A method of preventing, treating, managing, or ameliorating a respiratory tract infection or one or more symptoms thereof comprising administering to a subject in need thereof a therapeutically effective amount of a TLR5 agonist. 
     
     
         25 . The method of  claim 24 , wherein the TLR5 agonist is selected from the group consisting of small organic molecules; antibodies, aptamers or polypeptides. 
     
     
         26 . The method of  claim 25 , wherein the polypeptide is a flagellin polypeptide. 
     
     
         27 . The method of  claim 26 , wherein said flagellin polypeptide is isolated from a bacterium selected from the group consisting of  Escherichia, Enterobacter, Erwinia, Klebsiella, Proteus, Salmonella, Serratia, Shigella, Bacillus, Pseudomonas , and  Streptomyces.    
     
     
         28 . The method of  claim 25 , wherein an amino acid sequence of said flagellin polypeptide is selected from the group consisting of SEQ ID NO:1; SEQ ID NO:2; SEQ ID NO:3; an amino acid sequence at least 90% identical to SEQ ID NO: 1, SEQ ID NO:2 or SEQ ID NO:3; an amino acid sequence at least 95% identical to SEQ ID NO: 1, SEQ ID NO:2 or SEQ ID NO:3; an amino acid sequence at least 97% identical to SEQ ID NO: 1, SEQ ID NO:2 or SEQ ID NO:3; an amino acid sequence at least 98% identical to SEQ ID NO: 1, SEQ ID NO:2 or SEQ ID NO:3; and an amino acid sequence at least 99% identical to SEQ ID NO: 1, SEQ ID NO:2, or SEQ ID NO:3. 
     
     
         29 . The method of  claim 25 , wherein said flagellin polypeptide comprises: a) a N-terminal peptide having at least 90% amino acid identity with an amino acid sequence starting from the amino acid residue located at position 1 of SEQ ID NO:3 and ending at an amino acid residue selected from the group consisting of any one of the amino acid residues located at positions 99 to 173 of SEQ ID NO:3; and b) a C-terminal peptide having at least 90% amino acid identity with the amino acid sequence starting at an amino acid residue selected from the group consisting of any one of the amino acid residues located at positions 401 to 406 of SEQ ID NO:3 and ending at the amino acid residue located at position 494 of SEQ ID NO:3, wherein: the N-terminal peptide is directly linked to the C-terminal peptide, or the N-terminal peptide and the C-terminal peptide are indirectly linked, one to the other, through a spacer chain. 
     
     
         30 . The method of  claim 29 , wherein the N-terminal peptide is selected from the group consisting of amino acid sequence 1-99 of SEQ ID NO:3; amino acid sequence 1-137 of SEQ ID NO:3, amino acid sequence 1-160 of SEQ ID NO:3; and amino acid sequence 1-173 of SEQ ID NO:3. 
     
     
         31 . The method of  claim 29 , wherein said C-terminal peptide is selected from the group consisting of amino acid sequence 401-494 of SEQ ID NO:3 and amino acid sequence 406-494 of SEQ ID NO:3. 
     
     
         32 . The method of  claim 29 , wherein said N-terminal and C-terminal peptides are selected from the group consisting of: amino acid sequence 1-173 of SEQ ID NO:3 and amino acid sequence 401-494 of SEQ ID NO:3, respectively; amino acid sequence 1-160 of SEQ ID NO:3 and amino acid sequence 406-494 of SEQ ID NO:3, respectively; and amino acid sequence 1-137 of SEQ ID NO:3 and amino acid sequence 406-494 of SEQ ID NO:3, respectively. 
     
     
         33 . The method of  claim 29 , wherein the N-terminal peptide and the C-terminal peptide are indirectly linked, one to the other, through an intermediate spacer chain comprising a peptide sequence NH2-GIy-AIa-AIa-GIy-COOH (SEQ ID NO:4). 
     
     
         34 . The method of  claim 29 , wherein the asparagine amino acid residue located at position 488 of SEQ ID NO:3 is replaced by a serine. 
     
     
         35 . The method of  claim 29 , wherein said flagellin polypeptide comprises an additional methionine residue at the N-terminal end. 
     
     
         36 . The method of  claim 29 , wherein said respiratory tract infection is selected from the group consisting of viral infections, bacterial infections and fungal infections. 
     
     
         37 . The method of  claim 36 , wherein said viral infection is caused by a virus selected from the group consisting of retrovirus, herpes virus, arenavirus, paramyxovirus, adenovirus, bunyavirus, comavirus, Filovirus, flavivirus, hepadnaviruses, orthomyovirus, papovavirus, picornavirus, poxviruses, reovirus, togavirus, and rhabdovirus. 
     
     
         38 . The method of  claim 36 , wherein said bacterial infection is caused by a bacterium selected from the group consisting of Aquaspirillum, Azospirillum, Azotobacteraceae, Bacteroidaceae,  Bartonella, Bdellovibrio, Campylobacter, Chlamydia, Clostridium , Enterobacteriaceae, Edwardsiella,  Enterobacter aerogenes, Erwinia, Escherichia coli, Hafnia, Klebsiella, Morganella, Proteus vulgaris, Providencia, Salmonella, Serratia marcescens, Shigella flexneri, Gardinella, Haemophilus influenzae , Halobacteriaceae,  Helicobacter, Legionallaceae, Listeria , Methylococcaceae, mycobacteria, Neisseriaceae, Oceanospirillum, Pasteurellaceae,  Pneumococcus, Pseudomonas, Rhizobiaceae, Spirillum, Spirosomaceae, Staphylococcus, Streptococcus, Helicobacter , and Vampirovibrio. 
     
     
         39 . The method of  claim 36 , wherein said fungal infection is caused by a fungus selected from the group consisting of  Absidia, Aspergillus, Blastomyces dermatitidis, Candida, Coccidioides immitis, Conidiobolus, Cryptococcus neoforms, Cunninghamella, Histoplasma capsulatum, Mucor pusillus, Paracoccidioides brasiliensis, Pseudallescheria boydii, Pneumocystis carinii, Rhizopus, Saccharomyces , and  Sporothrix schenckii.    
     
     
         40 . The pharmaceutical composition of  claim 21 , wherein the TLR5 agonist is selected from the group consisting of small organic molecules; antibodies, aptamers or polypeptides. 
     
     
         41 . The pharmaceutical composition of  claim 40 , wherein the polypeptide is a flagellin polypeptide. 
     
     
         42 . The pharmaceutical composition of  claim 41 , wherein said flagellin polypeptide is isolated from a bacterium selected from the group consisting of  Escherichia, Enterobacter, Erwinia, Klebsiella, Proteus, Salmonella, Serratia, Shigella, Bacillus, Pseudomonas , and  Streptomyces.    
     
     
         43 . The pharmaceutical composition of  claim 41 , wherein an amino acid sequence of said flagellin polypeptide is selected from the group consisting of SEQ ID NO:1; SEQ ID NO:2; SEQ ID NO:3; an amino acid sequence at least about 90% identical to SEQ ID NO: 1, SEQ ID NO:2 or SEQ ID NO:3; an amino acid sequence at least about 95% identical to SEQ ID NO: 1, SEQ ID NO:2 or SEQ ID NO:3; an amino acid sequence at least about 97% identical to SEQ ID NO: 1, SEQ ID NO:2 or SEQ ID NO:3; an amino acid sequence at least about 98% identical to SEQ ID NO: 1, SEQ ID NO:2 or SEQ ID NO:3; and an amino acid sequence at least about 99% identical to SEQ ID NO: 1, SEQ ID NO:2, or SEQ ID NO:3. 
     
     
         44 . The pharmaceutical composition of  claim 41 , wherein said flagellin polypeptide comprises: a) a N-terminal peptide having at least 90% amino acid identity with the amino acid sequence starting from the amino acid residue located at position 1 of SEQ ID NO:3 and ending at an amino acid residue selected from the group consisting of any one of the amino acid residues located at positions 99 to 173 of SEQ ID NO:3; and b) a C-terminal peptide having at least 90% amino acid identity with the amino acid sequence starting at an amino acid residue selected from the group consisting of any one of the amino acid residues located at positions 401 to 406 of SEQ ID NO:3 and ending at the amino acid residue located at position 494 of SEQ ID NO:3, wherein: the N-terminal peptide is directly linked to the C-terminal peptide, or the N-terminal peptide and the C-terminal peptide are indirectly linked, one to the other, through a spacer chain. 
     
     
         45 . The pharmaceutical composition of  claim 44 , wherein the N-terminal peptide is selected from the group consisting of amino acid sequence 1-99 of SEQ ID NO:3; amino acid sequence 1-137 of SEQ ID NO:3, amino acid sequence 1-160 of SEQ ID NO:3; and amino acid sequence 1-173 of SEQ ID NO:3. 
     
     
         46 . The method of  claim 45 , wherein said C-terminal peptide is selected from the group consisting of amino acid sequence 401-494 of SEQ ID NO:3 and amino acid sequence 406-494 of SEQ ID NO:3. 
     
     
         47 . The method of  claim 44 , wherein said N-terminal and C-terminal peptides are selected from the group consisting of: amino acid sequence 1-173 of SEQ ID NO:3 and amino acid sequence 401-494 of SEQ ID NO:3, respectively; amino acid sequence 1-160 of SEQ ID NO:3 and amino acid sequence 406-494 of SEQ ID NO:3, respectively; and amino acid sequence 1-137 of SEQ ID NO:3 and amino acid sequence 406-494 of SEQ ID NO:3, respectively. 
     
     
         48 . The method of  claim 44 , wherein the N-terminal peptide and the C-terminal peptide are indirectly linked, one to the other, through an intermediate spacer chain comprising a peptide sequence NH2-GIy-AIa-AIa-GIy-COOH (SEQ ID NO:4). 
     
     
         49 . The method of  claim 43 , wherein the asparagine amino acid residue located at position 488 of SEQ ID NO:3 is replaced by a serine. 
     
     
         50 . The method of  claim 41 , wherein said flagellin polypeptide comprises an additional methionine residue at the N-terminal end. 
     
     
         51 . The pharmaceutical composition of  claim 22 , wherein said topical administration is intranasal administration or pulmonary administration.