Influenza virus inhibiting peptides

Abstract

The present invention provides a pharmaceutical composition for the treatment or prevention of an influenza infection. The composition comprises an isolated polypeptide including a sequence of at least 8 contiguous amino acid residues of the fusion initiation region (FIR) of an influenza hemagglutinin 2 protein or a peptide analog of the sequence. The FIR is a segment of the full length hemagglutinin 2 protein which is bounded by an amino-terminal region within the amino-terminal alpha-helix thereof and a carboxy terminus within the carboxy-terminal alpha-helix thereof, with a cysteine loop therebetween. The amino-terminal region of the FIR comprises a portion of the final 10 to 20 amino acid residues of the amino-terminal alpha-helix of the hemagglutinin 2 protein, and includes 3 or 4 hydrophobic amino acid residues, a positively-charged amino acid residue, a negatively-charged amino acid residue, and an aromatic amino acid residue. The carboxy terminus of the FIR is the carboxy terminus of the first peptide sequence of the hemagglutinin 2 protein beyond the amino terminal helix, which exhibits a positive Wimley-White interfacial hydrophobicity.

1 . A pharmaceutical composition for the treatment or prevention of an influenza infection comprising:
 an isolated polypeptide including at least 8 contiguous amino acid residues of the fusion initiation region (FIR) of an influenza hemagglutinin 2 protein; wherein the hemagglutinin 2 protein includes an amino-terminal alpha-helix and a carboxy-terminal alpha-helix; and the FIR is a segment of the full length hemagglutinin 2 protein which is bounded by an amino-terminal region within the amino-terminal alpha-helix and a carboxy terminus within the carboxy-terminal alpha-helix, with a cysteine loop therebetween; and wherein:   the amino-terminal region of the FIR comprises a portion of the final 10 to 20 amino acid residues of the amino-terminal alpha-helix of the hemagglutinin 2 protein, and includes 3 or 4 hydrophobic amino acid residues, a positively-charged amino acid residue, a negatively-charged amino acid residue, and an aromatic amino acid residue; and   the carboxy terminus of the FIR is the carboxy terminus of the first peptide sequence of the hemagglutinin 2 protein beyond the amino terminal helix, which exhibits a positive Wimley-White interfacial hydrophobicity.   
     
     
         2 . The composition of  claim 1  wherein the polypeptide comprises 8 to 40 contiguous amino acid residues of the FIR of the influenza hemagglutinin 2 protein. 
     
     
         3 . The composition of  claim 1  wherein the hemagglutinin 2 protein is an influenza
 A hemagglutinin 2 protein.   
     
     
         4 . The composition of  claim 1  wherein the polypeptide includes a hydrophobic group at the amino-terminus thereof. 
     
     
         5 . The composition of  claim 1  wherein the polypeptide includes a macromolecular carrier at the amino-terminus thereof. 
     
     
         6 . The composition of  claim 5  wherein the macromolecular carrier is selected from the group consisting of a lipid conjugate, a polyethylene glycol moiety, and a carbohydrate moiety. 
     
     
         7 . The composition of  claim 1  wherein the polypeptide includes a hydrophobic group at the carboxy-terminus thereof. 
     
     
         8 . The composition of  claim 1  wherein the polypeptide includes a macromolecular carrier at the carboxy-terminus thereof. 
     
     
         9 . The composition of  claim 8  wherein the macromolecular carrier is selected from the group consisting of a lipid conjugate, a polyethylene glycol moiety, and a carbohydrate moiety. 
     
     
         10 . The composition of  claim 1  wherein the polypeptide is capable of binding to the FIR of the influenza virus with a dissociation constant, K d , of at least about 9×10 −6 . 
     
     
         11 . A pharmaceutical composition for the treatment or prevention of an influenza infection comprising:
 an isolated polypeptide including a sequence of at least 8 contiguous amino acid residues of the fusion initiation region (FIR) of an influenza A hemagglutinin 2 protein or a peptide analog of the sequence; wherein the hemagglutinin 2 protein includes an amino-terminal alpha-helix and a carboxy-terminal alpha-helix; and the FIR is a segment of the full length hemagglutinin 2 protein which is bounded by an amino-terminal region within the amino-terminal alpha-helix and a carboxy terminus within the carboxy-terminal alpha-helix, with a cysteine loop therebetween; and wherein:   the amino-terminal region of the FIR comprises a portion of the final 10 to 20 amino acid residues of the amino-terminal alpha-helix of the hemagglutinin 2 protein, and includes 3 or 4 hydrophobic amino acid residues, a positively-charged amino acid residue, a negatively-charged amino acid residue, and an aromatic amino acid residue; and   the carboxy terminus of the FIR is the carboxy terminus of the first peptide sequence of the hemagglutinin 2 protein beyond the amino terminal helix, which exhibits a positive Wimley-White interfacial hydrophobicity.   
     
     
         12 . The composition of  claim 11  wherein the polypeptide comprises a sequence of 8 to 40 contiguous amino acid residues of the FIR of the influenza hemagglutinin 2 protein or a peptide analog of the sequence. 
     
     
         13 . The composition of  claim 11  wherein the hemagglutinin 2 protein is an influenza
 A hemagglutinin 2 protein.   
     
     
         14 . The composition of  claim 11  wherein the polypeptide includes a hydrophobic group at the amino-terminus thereof. 
     
     
         15 . The composition of  claim 11  wherein the polypeptide includes a macromolecular carrier at the amino-terminus thereof. 
     
     
         16 . The composition of  claim 15  wherein the macromolecular carrier is selected from the group consisting of a lipid conjugate, a polyethylene glycol moiety, and a carbohydrate moiety. 
     
     
         17 . The composition of  claim 11  wherein the polypeptide includes a hydrophobic group at the carboxy-terminus thereof. 
     
     
         18 . The composition of  claim 11  wherein the polypeptide includes a macromolecular carrier at the carboxy-terminus thereof. 
     
     
         19 . The composition of  claim 18  wherein the macromolecular carrier is selected from the group consisting of a lipid conjugate, a polyethylene glycol moiety, and a carbohydrate moiety. 
     
     
         20 . The composition of  claim 11  wherein the polypeptide includes a peptide analog, wherein the analog includes one or more conservative amino acid substitution in the sequence of the at least 8 contiguous amino acid residues of the FIR. 
     
     
         21 . The composition of  claim 11  wherein the polypeptide includes a peptide analog, wherein the analog includes one or more D-amino acid substitutions in the amino acid residue sequence of the at least 8 contiguous amino acid residues of the FIR. 
     
     
         22 . The composition of  claim 11  wherein the polypeptide is capable of binding to the FIR of the influenza virus with a dissociation constant, K d , of at least about 9×10 −6 .