US 10,138,276 B2 · 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).

A composition, the composition 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 Gln, 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.

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Inhibition of TCR signaling with peptide variants

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Inhibition of TCR signaling with peptide variants

Life of this patent

Abstract

Claims13