Inhibition Of TCR Signaling With Peptide Variants

Abstract

The present invention provides compositions comprising peptides derived from amino acid sequences (or from combinations thereof) of fusion and other protein regions of various viruses, including but not limited to, severe acute respiratory syndrome coronavirus, herpesvirus saimiri, human herpesvirus 6, Lassa virus, lymphocytic choriomeningitis virus, Mopeia virus, Tacaribe virus, Friend murine leukemia virus; human T lymphotropic virus type 1; herpesvirus ateles; Marburg virus; Sudan Ebola virus; Zaire Ebola virus, and comprising L- and/or D-amino acids and combinations thereof, which affect T cells by acting on the T cell antigen receptor (TCR). More specifically, the peptides act on the TCRαβ-CD3δε-CD3γε-ζζ signaling complex. Yet more specifically, the peptides act on the TCRα/CD3δε/ζζ signaling module of TCR. The present invention further relates to the prevention and therapy of various T cell-related disease states involving the use of these compositions. Specifically, the compositions are useful in the treatment and/or prevention of a disease or condition where T cells are involved or recruited. The compositions of the present invention also are useful in the production of medical devices comprising peptide matrices (for example, medical implants and implantable devices).

1 - 11 . (canceled) 
     
     
         12 . A method, comprising:
 a) providing;
 i) a patient having at least one symptom of a disease or a medical condition where T cells are involved or recruited; and 
 ii) a peptide inhibitor comprising a peptide consisting of no more than 25 amino acids according to formula:
   R1-Y1-Y2-Y3-Y4-Y5-Y6-Y7-Y8-Y9-Y10-Y11-R2, wherein: 
 
 R1 is selected from the group consisting of N-terminal sugar conjugate and N-terminal lipid conjugate; 
 Y1 is selected from the group consisting of Arg, Arg-Arg, Arg-Arg-Arg and Arg-Arg-Arg-Arg (SEQ ID NO: 82); 
 Y2 is selected from the group consisting of Lys, Lys-Lys, Lys-Lys-Lys and Lys-Lys-Lys-Lys (SEQ ID NO: 83); 
 Y3 is selected from the group consisting of A1-A2-A3, A*1-A*2-A*3-A*4 and A**1-A**2-A**3-A**4, wherein:
 A1 is absent or is selected from the group consisting of Val, Ile, Leu and a two amino acid peptide, said peptide consisting of Val, Ile and Leu in any combination; 
 A2 is absent or is selected from the group consisting of Gly and Met; 
 A3 is absent or is selected from the group consisting of Phe, Leu, Ile and Tyr; 
 A*1 is absent or is selected from the group consisting of Arg, Gly, Leu and Ile; 
 A*2 is absent or is selected from the group consisting of Asn, Gln and Ala; 
 A*3 is absent or is selected from the group consisting of Ile, Leu and Ser; 
 A*4 is absent or is selected from the group consisting of Val, Asn and Gly; 
 A**1 is absent or is selected from the group consisting of Ala, Pro, Cys, Thr, Asn, Met, Glu and a two amino acid peptide, said peptide consisting of Ala, Pro, Cys, Thr, Asn, Met and Glu in any combination; 
 A**2 is absent or is selected from the group consisting of Thr, Ser, Gly, Ala, Tyr, Pro, Ile, a two amino acid peptide and a three amino acid peptide, said peptide consisting of Thr, Ser, Gly, Ala, Tyr, Pro and Ile in any combination; 
 A**3 is absent or is selected from the group consisting of Gly, Met, Cys, Pro, Leu, Ile, Gln and a two amino acid peptide, said peptide consisting of Gly, Met, Cys, Pro, Leu, Ile and Gln in any combination; 
 A**4 is absent or is selected from the group consisting of Ala, Thr, Glu, Asn and Ser; 
 
 Y4 is a positively charged amino acid selected from the group comprising Arg, Lys and His; 
 Y5 is selected form the group consisting of C1, C*1 and C**, wherein:
 C1 is a four amino acid peptide consisting of Leu, Ile, Thr and Pro in any combination; 
 C*1 is a three amino acid peptide consisting of Asp, Leu, Ile, Arg, Lys, Ser, Val and Glu in any combination; 
 C** is an eight amino acid peptide; 
 
 Y6 is a positively charged amino acid selected from the group comprising Arg, Lys and His; 
 Y7 is selected from the group consisting of E1-E2-E3, E* 1 and E** 1-E**2-E**3, wherein:
 E1 is Val or Tyr; 
 E2 is absent or is selected from the group consisting of Ala and Phe; 
 E3 is absent or Gly; 
 E* 1 is a three amino acid peptide consisting of Asp, Asn, Leu, Lys, Ile, Val and Glu in any combination; 
 E**1 is absent or is selected from the group consisting of Gin, Cys, Glu, Trp and Arg; 
 E**2 is absent or is selected from the group consisting of Leu, Ile, Phe, Gly and Lys; 
 E**3 is absent or is selected from the group consisting of Gly and Thr; 
 
 Y8 is selected form the group consisting of F1-F2, F*1 and F**1, wherein:
 F1 is absent or is selected from the group consisting of Gly, Phe, Asn, a two amino acid peptide and a three amino acid peptide, said peptide consisting of Gly, Phe and Asn in any combination; 
 F2 is absent or is selected from the group consisting of Leu, Phe, Ile, Met, Thr, Gln, a two amino acide peptide, a three amino acide peptide, a four amino acide peptide and a five amino acide peptide, said peptide consisting of Leu, Phe, Ile, Met, Thr and Gln in any combination; 
 F*1 is a positively charged amino acid selected from the group comprising Arg, Lys and His; 
 F**1 is absent or is selected from the group consisting of Asn, Leu, Ile, Thr, Phe, Val, a two amino acid peptide, a three amino acid peptide and a four amino acid peptide said peptide consisting of Asn, Leu, Ile, Thr, Phe and Val in any combination; 
 
 Y9 is absent or G*1-G*2, wherein:
 G* 1 is selected from the group consisting of Ile, Leu and Asp; 
 G*2 is absent or is selected from the group consisting of Asn and Thr; 
 
 Y10 is absent or is selected from the group consisting of Arg, Arg-Arg, Arg-Arg-Arg and Arg-Arg-Arg-Arg (SEQ ID NO: 82); 
 Y11 is absent or is selected from the group consisting of Lys, Lys-Lys, Lys-Lys-Lys and Lys-Lys-Lys-Lys (SEQ ID NO: 83); and 
 R2 is absent or is C-terminal lipid conjugate; and 
   b) administering said peptide inhibitor to said patient under conditions such that said at least one symptom is reduced.   
     
     
         13 . The method of  claim 12 , wherein said disease or said medical condition comprises an autoimmune disorder. 
     
     
         14 . The method of  claim 13 , wherein said autoimmune disorder is selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, type I diabetes, inflammatory bowel disease, Crohn's disease, primary biliary cirrhosis, chronic active hepatitis, atopic dermatitis, psoriasis, pemphigus vulgaris and autoimmune pericarditis. 
     
     
         15 . The method of  claim 12 , wherein:
 said R1 is selected from one of the group consisting of N-terminal sugar conjugate and N-terminal lipid conjugate;   said Y1 is selected from one of the group consisting of Arg, Arg-Arg, Arg-Arg-Arg and Arg-Arg-Arg-Arg (SEQ ID NO: 82);   said Y2 is selected from one of the group consisting of Lys, Lys-Lys, Lys-Lys-Lys and Lys-Lys-Lys-Lys (SEQ ID NO: 83);   said Y3 is said A1-A2-A3, wherein;
 A1 is absent or is selected from one of the group consisting of Val, Ile, and Leu or a peptide consisting of two amino acids, said two amino acids being selected from the group consisting of Val, Ile and Leu in any combination; 
 A2 is absent or is selected from one of the group consisting of Gly and Met; 
 A3 is absent or is selected from one of the group consisting of Phe, Leu, Ile and Tyr; 
   said Y4 is a positively charged amino acid selected from one of the group consisting of Arg, Lys and His;   said Y5 is a four amino acid peptide consisting of Leu, Ile, Thr and Pro in any combination;   said Y6 is a positively charged amino acid selected from one of the group consisting of Arg, Lys and His;   said Y7 is said E1-E2-E3, wherein
 E1 is Val or Tyr; 
 E2 is absent or is Ala or Phe; 
 E3 is absent or Gly; 
   said Y8 is said F1-F2, wherein;
 F1 is absent or is selected from the group consisting of a single amino acid, a two amino acid peptide and a three amino acid peptide, said amino acid being selected from the group consisting of Gly, Phe and Asn in any combination; 
 F2 is absent or is selected from the group consisting of a single amino acid, a two amino acid peptide, a three amino acid peptide, a four amino acid peptide and a five amino acid peptide, said amino acid being selected from the group consisting of Leu, Phe, Ile, Met, Thr and Gln in any combination; 
   said Y9 is absent;   said Y10 is absent or is selected from the group consisting of Arg, Arg-Arg, Arg-Arg-Arg, and Arg-Arg-Arg-Arg (SEQ ID NO: 82);   said Y11 is absent or is selected from the group consisting of Lys, Lys-Lys-, Lys-Lys-Lys and Lys-Lys-Lys-Lys (SEQ ID NO: 83); and   said R2 is absent or is said C-terminal lipid conjugate.   
     
     
         16 . The method of  claim 12 , wherein said N-terminal sugar conjugate is 1-amino-glucose succinate. 
     
     
         17 . The method of  claim 12 , wherein said N-terminal lipid conjugate is selected from the group consisting of 2-aminododecanoate and myristoylate conjugates. 
     
     
         18 . The method of  claim 12 , wherein said C-terminal lipid conjugate is selected from the group consisting of Gly-Tris-monopalmitate, Gly-Tris-dipalmitate and Gly-Tris-tripalmitate conjugates. 
     
     
         19 . The method of  claim 12 , wherein said peptide inhibitor is attached to a carrier molecule. 
     
     
         20 . The method of  claim 12 , wherein said peptide inhibitor is conjugated at a free amine group with a polyalkylene glycol. 
     
     
         21 . The method of  claim 20 , wherein the polyalkylene glycol is polyethylene glycol. 
     
     
         22 . The method of  claim 12 , wherein one or more amino acids is a D-amino acid. 
     
     
         23 . The method of  claim 12 , wherein said peptide inhibitor comprises at least one amino acid selected from the group consisting of L-amino acids and D-amino acids. 
     
     
         24 . The method of  claim 12 , wherein said peptide inhibitor has immunosuppressive activity. 
     
     
         25 . The method of  claim 12 , wherein said peptide inhibitor has an amino acid sequence selected from the group consisting of Myr-Gly-Arg-Lys-Leu-Gly-Tyr-Lys-Leu-Leu-Thr-Ile-Arg-Tyr-Ala-Asn-Leu (SEQ ID NO: 96), Myr-Gly-Arg-Lys-Gly-Tyr-Arg-Pro-Thr-Pro-Ile-Arg-Val-Ala-Phe-Gly-Asn-Leu (SEQ ID NO: 97), Myr-Gly-Arg-Lys-Leu-Val-Leu-Gly-Lys-Ala-Ser-Val-Pro-Ala-Thr-Gly-Ser-Arg-Leu-Val-Ser-Lys-Tyr-Lys (SEQ ID NO: 98) and Myr-Gly-Arg-Lys-Gly-Tyr-Leu-Gly-Pro-Gly-Lys-Asp-Leu-Ser-Arg-Val-Asn-Val-Lys-Gly-Arg (SEQ ID NO: 99). 
     
     
         26 . The method of  claim 12 , wherein said peptide inhibitor is a T cell receptor inhibitor