Use of a polypeptide as cellular receptor for adenoviruses

Abstract

The subject of the present invention is the use of a polypeptide comprising at least 6 continuous amino acids of the sequence as shown in the sequence identifiers 1 to 5 as cellular receptor and/or coreceptor for adenoviruses. It also relates to the use of a cell capable of expressing such a polypeptide as well as that of a ligand capable of influencing the attachment of an adenovirus to a host cell and/or its entry into the said host cell. Finally, it also relates to a method for selecting or identifying a cellular receptor for a virus or the part of a viral protein which determines the attachment of the virus to its cellular receptor as well as to the use of a bifunctional ligand to target an adenovirus to a host cell carrying, at its surface, a surface protein other than the natural cellular receptor for the said adenovirus.

1 . Use of a polypeptide comprising an amino acid sequence homologous or identical to at least 6 continuous amino acids of the sequence as shown: 
 (a) in SEQ ID NO: 1 starting with the leucine residue at position 1 and ending with the glutamine residue at position 25,    (b) in SEQ ID NO: 2 starting with the asparagine residue at position 1 and ending with the asparagine residue at position 26,    (c) in SEQ ID NO: 3 starting with the valine residue at position 1 and ending with the asparagine residue at position 25,    (d) in SEQ ID NO: 4 starting with the serine residue at position 1 and ending with the arginine residue at position 25, and/or    (e) in SEQ ID NO: 5 starting with the asparagine residue at position 1 and ending with the serine residue at position 25;    to allow or facilitate the attachment of an adenovirus to a host cell and/or the entry of the said adenovirus into the said host cell.    
     
     
         2 . Use according to  claim 1 , characterized in that the polypeptide comprises an amino acid sequence homologous or identical to at least 6 continuous amino acids of the sequence as shown in SEQ ID NO: 1 starting with the leucine residue at position 1 and ending with the glutamine residue at position 25.  
     
     
         3 . Use according to  claim 2 , characterized in that the polypeptide comprises an amino acid sequence homologous or identical to all or part of an antigen of the class I major histocompatibility complex (MHC-I) and, preferably, of the heavy chain of the said MHC-I.  
     
     
         4 . Use according to  claim 3 , characterized in that the polypeptide comprises an amino acid sequence homologous or identical to all or part of the α2 domain of the said heavy chain.  
     
     
         5 . Use according to  claim 3  or  4 , characterized in that the polypeptide comprises an amino acid sequence homologous or identical to all or part of an HLA A, B, C, D, E or F antigen.  
     
     
         6 . Use according to  claim 1 , characterized in that the polypeptide comprises an amino acid sequence homologous or identical to at least 6 continuous amino acids of the sequence as shown: 
 in SEQ ID NO: 2 starting with the asparagine residue at position 1 and ending with the asparagine residue at position 26,    in SEQ ID NO: 3 starting with the valine residue at position 1 and ending with the asparagine residue at position 25,    in SEQ ID NO: 4 starting with the serine residue at position 1 and ending with the arginine residue at position 25, and/or    in SEQ ID NO: 5 starting with the asparagine residue at position 1 and ending with the serine residue at position 25.    
     
     
         7 . Use according to  claim 6 , characterized in that the said polypeptide comprises an amino acid sequence homologous or identical to all or part of fibronectin.  
     
     
         8 . Use according to  claim 7 , characterized in that the said polypeptide comprises an amino acid sequence homologous or identical to all or part of at least one type III module of fibronectin.  
     
     
         9 . Use according to one of  claims 1  to  8 , characterized in that the said adenovirus is of serotype C.  
     
     
         10 . Use according to  claim 9 , characterized in that the said adenovirus is of serotype 2 or 5.  
     
     
         11 . Cell capable of expressing a polypeptide as defined according to one of  claims 1  to  10 .  
     
     
         12 . Cell according to  claim 11 , characterized in that the said cell overexpresses the said polypeptide.  
     
     
         13 . Use of a cell according to  claim 11  or  12 , to allow or facilitate the attachment of an adenovirus to the said cell and/or the entry of the said adenovirus into the said cell.  
     
     
         14 . Use of a ligand to influence the attachment of an adenovirus to a host cell and/or the entry of the said adenovirus into the said host cell which are mediated by a polypeptide as defined in one of  claims 1  to  10 .  
     
     
         15 . Use of a ligand according to  claim 14 , to negatively influence the attachment of an adenovirus to the said host cell and/or the entry of the said adenovirus into the said host cell which are mediated by a polypeptide as defined according to one of  claims 1  to  5  and  9  and  10 .  
     
     
         16 . Use of a ligand according to  claim 15 , characterized in that the said ligand comprises an amino acid sequence homologous or identical to at least 6 continuous amino acids contained in the sequence as shown in SEQ ID NO: 6 starting with the arginine residue at position 1 and ending with the arginine residue at position 20.  
     
     
         17 . Use of a ligand according to  claim 14 , to positively influence the attachment of an adenovirus to the said host cell and/or the entry of the said adenovirus into the said host cell which are mediated by a polypeptide as defined according to one of claims  1  and  6  to  10 .  
     
     
         18 . Use of a ligand according to  claim 17 , characterized in that the said ligand comprises an amino acid sequence homologous or identical to at least 6 continuous amino acids contained in the sequence as shown in SEQ ID NO: 7 starting with the arginine residue at position 1 and ending with the serine residue at position 20.  
     
     
         19 . Use of a ligand according to one of  claims 14  to  18 , characterized in that the said ligand has a dissociation constant (kd) with respect to the said adenovirus of 0.01 to 100 nM, and in particular of 0.1 to 50 nM.  
     
     
         20 . Ligand as defined in  claim 16 ,  18  or  19 .  
     
     
         21 . Use of a ligand according to  claim 14 , characterized in that the said ligand is of adenoviral origin.  
     
     
         22 . Use according to  claim 21 , characterized in that the said ligand is derived from the fiber of an adenovirus and, in particular, from the head domain.  
     
     
         23 . Use according to  claim 22  to interact with a polypeptide as defined according to one of  claims 1  to  5  and  9  and  10 , characterized in that the said ligand is derived from the fiber of a serotype 5 adenovirus and comprises an amino acid sequence homologous or identical to at least 6 continuous amino acids of the sequence as shown in SEQ ID NO: 8 starting with the leucine residue at position 1 and ending with the aspartic acid residue at position 18.  
     
     
         24 . Use according to  claim 22  to interact with a polypeptide as defined according to one of  claims 1  to  5  and  9  and  10 , characterized in that the said ligand is derived from the fiber of a serotype 2 adenovirus and comprises an amino acid sequence homologous or identical to at least 6 continuous amino acids of the sequence as shown in SEQ ID NO: 9 starting with the threonine residue at position 1 and ending with the valine residue at position 16.  
     
     
         25 . Use according to  claim 22  to interact with a polypeptide as defined according to one of claims  1  and  6  to  10 , characterized in that the said ligand is derived from the fiber of a serotype 5 adenovirus and comprises an amino acid sequence homologous or identical to at least 6 continuous amino acids of the sequence as shown in SEQ ID NO: 10 starting with the leucine residue at position 1 and ending with the threonine residue at position 14.  
     
     
         26 . Use according to  claim 22  to interact with a polypeptide as defined according to one of claims  1  and  6  to  10 , characterized in that the said ligand is derived from the fiber of a serotype 2 adenovirus and comprises an amino acid sequence homologous or identical to at least 6 continuous amino acids of the sequence as shown in SEQ ID NO: 11 starting with the asparagine residue at position 1 and ending with the asparagine residue at position 13.  
     
     
         27 . Use of a ligand according to one of  claims 14  to  26 , for the preparation of a medicament intended to inhibit or reduce an infection by an adenovirus.  
     
     
         28 . Use of a ligand according to one of  claims 14  to  26 , for the preparation of a medicament intended to promote or facilitate an infection by an adenovirus, and in particular a recombinant adenovirus.  
     
     
         29 . Method for selecting or identifying a cellular receptor for a virus in an appropriate sample, comprising the following steps: 
 (a) immobilization, onto an inert support, of a reagent of viral origin comprising all or part of a surface protein of the said virus which determines the attachment of the said virus to the said cellular receptor,    (b) incubation with the said sample for a determined time,    (c) elution of the sample retained in step (b) with all or part of an antibody directed against the said reagent of viral origin, and    (d) analysis of the sample eluted in step (c).    
     
     
         30 . Method for selecting or identifying the part of a viral protein which determines the attachment of a virus to a cellular receptor in an appropriate sample, comprising the following steps: 
 (a) immobilization, onto an inert support, of all or part of an antibody directed against the said viral protein,    (b) incubation with the said sample for a determined time,    (c) elution of the sample retained in step (b) with a reagent of viral origin comprising all or part of the said viral protein, and    (d) analysis of the sample eluted in step (c).    
     
     
         31 . Method according to  claim 29  or  30 , characterized in that the said sample is a peptide library or a phage library expressing peptide motifs.  
     
     
         32 . Method according to one of  claims 29  to  31 , characterized in that the said virus is an adenovirus, in particular of serotype C, the reagent of viral origin comprises to all or part of the fiber and, in particular, of the head of an adenovirus and the antibody is an inhibitor of the attachment of the virus to the surface of the host cell.  
     
     
         33 . Use of a bifunctional ligand for targeting an adenovirus to a cell surface protein other than the natural cellular receptor for the said adenovirus, the said bifunctional ligand comprising a first ligand part capable of interacting with the fiber of the said adenovirus, a second ligand part capable of interacting with the said cell surface protein and, optionally, a spacer between the said first and second ligand parts; the said first ligand part having the characteristics of the ligand as defined in  claims 14  to  20 .  
     
     
         34 . Use according to  claim 33 , according to which the said first ligand part comprises an amino acid sequence homologous or identical to at least 6 continuous amino acids contained in SEQ ID NO: 6 and more particularly has an amino acid sequence identical to SEQ ID NO: 6 starting with the arginine residue at position 1 and ending with the arginine residue at position 20.  
     
     
         35 . Use according to  claim 33  or  34 , according to which the said bifunctional ligand comprises an amino acid sequence homologous or identical to all or part of the sequence as shown: 
 (i) in SEQ ID NO: 22 starting at the arganine residue at position 1 and ending with the methionine residue at position 35, or  
 (ii) in SEQ ID NO: 23 starting at the lysine residue at position 1 and ending with the arginine residue at position 35.  
 
     
     
         36 . Bifunctional ligand as defined in one of  claims 33  to  35 .  
     
     
         37 . Cell carrying at its surface a bifunctional ligand according to claim  36 .