Thrombopoietic compounds
First Claim
Patent Images
1. A compound that binds to an mpl receptor comprising the structure
TMP1-(L1)n-TMP2 wherein the C-terminus of the TMP1 peptide is linked to the N-terminus of the TMP2 peptide, optionally via L1,wherein TMP1 and TMP2 are each independently selected from the group of core compounds comprising the structure selected from the group consisting of:
- a) X2-X3-X4-X5-X6-X7-X8-X9-X10,wherein,X2 is selected from the group consisting of Glu, Lys, and Val;
X3 is selected from the group consisting of Gly and Ala;
X4 is Pro;
X5 is selected from the group consisting of Thr and Ser;
X6 is selected from the group consisting of Leu, Ile, Val, Ala, and Phe;
X7 is selected from the group consisting of Arg and Lys;
X8 is selected from the group consisting of Gln, Asn, and Glu;
X9 is selected from the group consisting of Trp, Tyr, Cys, Ala, and Phe;
X10 is selected from the group consisting of Leu, Ile, Val, Ala, Phe, Met, and Lys;
b) X2-X3-X4-X5-X6-X7-X8-X9-X10,wherein,X2 is selected from the group consisting of Glu, Asp, Lys, and Val;
X3 is Ala;
X4 is Pro;
X5 is selected from the group consisting of Thr and Ser;
X6 is selected from the group consisting of Leu, Ile, Val, Ala, and Phe;
X7 is selected from the group consisting of Arg and Lys;
X8 is selected from the group consisting of Gln, Asn, and Glu;
X9 is selected from the group consisting of Trp, Tyr, Cys, Ala, and Phe;
X10 is selected from the group consisting of Leu, Ile, Val, Ala, Phe, Met, and Lys;
C) X2-X3-X4-X5-X6-X7-X8-X9-X10,wherein,X2 is selected from the group consisting of Glu, Asp, Lys, and Val;
X3 is selected from the group consisting of Gly and Ala;
X4 is Pro;
X5 is Ser;
X6 is selected from the group consisting of Leu, Ile, Val, Ala, and Phe;
X7 is selected from the group consisting of Arg and Lys;
X8 is selected from the group consisting of Gln, Asn, and Glu;
X9 is selected from the group consisting of Trp, Tyr, Cys, Ala, and Phe;
X10 is selected from the group consisting of Leu, Ile, Val, Ala, Phe, Met, and Lys;
d) X2-X3-X4-X5-X6-X7-X8-X9-X10,wherein,X2 is selected from the group consisting of Glu, Asp, Lys, and Val;
X3 is selected from the group consisting of Gly and Ala;
X4 is Pro;
X5 is selected from the group consisting of Thr and Ser;
X6 is selected from the group consisting of Ile, Val, Ala, and Phe;
X7 is selected from the group consisting of Arg and Lys;
X8 is selected from the group consisting of Gln, Asn, and Glu;
X9 is selected from the group consisting of Trp, Tyr, Cys, Ala, and Phe;
X10 is selected from the group consisting of Leu, Ile, Val, Ala, Phe, Met, and Lys;
e) X2-X3-X4-X5-X6-X7-X8-X9-X10,wherein,X2 is selected from the group consisting of Glu, Asp, Lys, and Val;
X3 is selected from the group consisting of Gly and Ala;
X4 is Pro;
X5 is selected from the group consisting of Thr and Ser;
X6 is selected from the group consisting of Leu, Ile, Val, Ala, and Phe;
X7 is Lys;
X8 is selected from the group consisting of Gln, Asn, and Glu;
X9 is selected from the group consisting of Trp, Tyr, Cys, Ala, and Phe;
X10 is selected from the group consisting of Leu, Ile, Val, Ala, Phe, Met, and Lys;
f) X2-X3-X4-X5-X6-X7-X8-X9-X10,wherein,X2 is selected from the group consisting of Glu, Asp, Lys, and Val;
X3 is selected from the group consisting of Gly and Ala;
X4 is Pro;
X5 is selected from the group consisting of Thr and Ser;
X6 is selected from the group consisting of Leu, Ile, Val, Ala, and Phe;
X7 is selected from the group consisting of Arg and Lys;
X8 is selected from the group consisting of Gln and Asn;
X9 is selected from the group consisting of Trp, Tyr, Cys, Ala, and Phe;
X10 is selected from the group consisting of Leu, Ile, Val, Ala, Phe, Met, and Lys;
g) X2-X3-X4-X5-X6-X7-X8-X9-X10,wherein,X2 is selected from the group consisting of Glu, Asp, Lys, and Val;
X3 is selected from the group consisting of Gly and Ala;
X4 is Pro;
X5 is selected from the group consisting of Thr and Ser;
X6 is selected from the group consisting of Leu, Ile, Val, Ala, and Phe;
X7 is selected from the group consisting of Arg and Lys;
X8 is selected from the group consisting of Gln, Asn, and Glu;
X9 is selected from the group consisting of Tyr, Cys, Ala, and Phe;
X10 is selected from the group consisting of Leu, Ile, Val, Ala, Phe, Met, and Lys; and
h) X2-X3-X4-X5-X6-X7-X8-X9-X10,wherein,X2 is selected from the group consisting of Glu, Asp, Lys, and Val;
X3 is selected from the group consisting of Gly and Ala;
X4 is Pro;
X5 is selected from the group consisting of Thr and Ser;
X6 is selected from the group consisting of Leu, Ile, Val, Ala, and Phe;
X7 is selected from the group consisting of Arg and Lys;
X8 is selected from the group consisting of Gln, Asn, and Glu;
X9 is selected from the group consisting of Trp, Tyr, Cys, Ala, and Phe;
X10 is selected from the group consisting of Leu, Val, Ala, Phe, Met, and Lys; and
wherein L1 is a linker; and
n is 0 or 1, wherein when n is 1, L1 is independently selected from the linker groups consisting of Yn, wherein Y is a naturally occurring amino acid or a stereoisomer thereof and n is 1 through 20;
and physiologically acceptable salts thereof.
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Accused Products
Abstract
The invention relates to the field of compounds, especially peptides or polypeptides, that have thrombopoietic activity. The peptides and polypeptides of the invention may be used to increase platelets or platelet precursors (e.g., megakaryocytes) in a mammal.
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Citations
8 Claims
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1. A compound that binds to an mpl receptor comprising the structure
TMP1-(L1)n-TMP2wherein the C-terminus of the TMP1 peptide is linked to the N-terminus of the TMP2 peptide, optionally via L1, wherein TMP1 and TMP2 are each independently selected from the group of core compounds comprising the structure selected from the group consisting of: -
a) X2-X3-X4-X5-X6-X7-X8-X9-X10, wherein, X2 is selected from the group consisting of Glu, Lys, and Val; X3 is selected from the group consisting of Gly and Ala; X4 is Pro; X5 is selected from the group consisting of Thr and Ser; X6 is selected from the group consisting of Leu, Ile, Val, Ala, and Phe; X7 is selected from the group consisting of Arg and Lys; X8 is selected from the group consisting of Gln, Asn, and Glu; X9 is selected from the group consisting of Trp, Tyr, Cys, Ala, and Phe; X10 is selected from the group consisting of Leu, Ile, Val, Ala, Phe, Met, and Lys; b) X2-X3-X4-X5-X6-X7-X8-X9-X10, wherein, X2 is selected from the group consisting of Glu, Asp, Lys, and Val; X3 is Ala; X4 is Pro; X5 is selected from the group consisting of Thr and Ser; X6 is selected from the group consisting of Leu, Ile, Val, Ala, and Phe; X7 is selected from the group consisting of Arg and Lys; X8 is selected from the group consisting of Gln, Asn, and Glu; X9 is selected from the group consisting of Trp, Tyr, Cys, Ala, and Phe; X10 is selected from the group consisting of Leu, Ile, Val, Ala, Phe, Met, and Lys; C) X2-X3-X4-X5-X6-X7-X8-X9-X10, wherein, X2 is selected from the group consisting of Glu, Asp, Lys, and Val; X3 is selected from the group consisting of Gly and Ala; X4 is Pro; X5 is Ser; X6 is selected from the group consisting of Leu, Ile, Val, Ala, and Phe; X7 is selected from the group consisting of Arg and Lys; X8 is selected from the group consisting of Gln, Asn, and Glu; X9 is selected from the group consisting of Trp, Tyr, Cys, Ala, and Phe; X10 is selected from the group consisting of Leu, Ile, Val, Ala, Phe, Met, and Lys; d) X2-X3-X4-X5-X6-X7-X8-X9-X10, wherein, X2 is selected from the group consisting of Glu, Asp, Lys, and Val; X3 is selected from the group consisting of Gly and Ala; X4 is Pro; X5 is selected from the group consisting of Thr and Ser; X6 is selected from the group consisting of Ile, Val, Ala, and Phe; X7 is selected from the group consisting of Arg and Lys; X8 is selected from the group consisting of Gln, Asn, and Glu; X9 is selected from the group consisting of Trp, Tyr, Cys, Ala, and Phe; X10 is selected from the group consisting of Leu, Ile, Val, Ala, Phe, Met, and Lys; e) X2-X3-X4-X5-X6-X7-X8-X9-X10, wherein, X2 is selected from the group consisting of Glu, Asp, Lys, and Val; X3 is selected from the group consisting of Gly and Ala; X4 is Pro; X5 is selected from the group consisting of Thr and Ser; X6 is selected from the group consisting of Leu, Ile, Val, Ala, and Phe; X7 is Lys; X8 is selected from the group consisting of Gln, Asn, and Glu; X9 is selected from the group consisting of Trp, Tyr, Cys, Ala, and Phe; X10 is selected from the group consisting of Leu, Ile, Val, Ala, Phe, Met, and Lys; f) X2-X3-X4-X5-X6-X7-X8-X9-X10, wherein, X2 is selected from the group consisting of Glu, Asp, Lys, and Val; X3 is selected from the group consisting of Gly and Ala; X4 is Pro; X5 is selected from the group consisting of Thr and Ser; X6 is selected from the group consisting of Leu, Ile, Val, Ala, and Phe; X7 is selected from the group consisting of Arg and Lys; X8 is selected from the group consisting of Gln and Asn; X9 is selected from the group consisting of Trp, Tyr, Cys, Ala, and Phe; X10 is selected from the group consisting of Leu, Ile, Val, Ala, Phe, Met, and Lys; g) X2-X3-X4-X5-X6-X7-X8-X9-X10, wherein, X2 is selected from the group consisting of Glu, Asp, Lys, and Val; X3 is selected from the group consisting of Gly and Ala; X4 is Pro; X5 is selected from the group consisting of Thr and Ser; X6 is selected from the group consisting of Leu, Ile, Val, Ala, and Phe; X7 is selected from the group consisting of Arg and Lys; X8 is selected from the group consisting of Gln, Asn, and Glu; X9 is selected from the group consisting of Tyr, Cys, Ala, and Phe; X10 is selected from the group consisting of Leu, Ile, Val, Ala, Phe, Met, and Lys; and h) X2-X3-X4-X5-X6-X7-X8-X9-X10, wherein, X2 is selected from the group consisting of Glu, Asp, Lys, and Val; X3 is selected from the group consisting of Gly and Ala; X4 is Pro; X5 is selected from the group consisting of Thr and Ser; X6 is selected from the group consisting of Leu, Ile, Val, Ala, and Phe; X7 is selected from the group consisting of Arg and Lys; X8 is selected from the group consisting of Gln, Asn, and Glu; X9 is selected from the group consisting of Trp, Tyr, Cys, Ala, and Phe; X10 is selected from the group consisting of Leu, Val, Ala, Phe, Met, and Lys; and wherein L1 is a linker; and n is 0 or 1, wherein when n is 1, L1 is independently selected from the linker groups consisting of Yn, wherein Y is a naturally occurring amino acid or a stereoisomer thereof and n is 1 through 20; and physiologically acceptable salts thereof. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8)
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8. The compound according to claim 1 wherein L1 comprises a Cys residue.
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Specification