Peptide and polypeptide inhibitors of complement C1s
First Claim
Patent Images
1. A polypeptide that inhibits complement C1s, wherein the polypeptide is characterized by the formula:
- “
P-N-[DE](2)-[YX1X2X3]-[DE](1,2)-[YX1X2X3]-[DE]-[YX1X2X3]-[DE](1,2),”
where amino acid residues in square brackets indicate alternative amino acids, numbers in parentheses indicate the number of amino acid residues, such that [DE](2) represents DD, EE, DE, or ED;
“
X1”
represents Phe-(p-CH2)SO3H, “
X2”
represents sulfated tyrosine, and “
X3”
represents 2-sulfotyrosine (SEQ ID NO;
127).
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Abstract
The complement system plays an important role in providing resistance to infections and in the pathogenesis of tissue injury. Yet an inappropriate activation of complement can result in a variety of disorders. The present invention provides C1s catalytic site-directed moieties, C1s exosite binding moieties, and bivalent polypeptide inhibitors comprising such moieties, which can be used to treat conditions characterized by inappropriate complement activation.
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Citations
23 Claims
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1. A polypeptide that inhibits complement C1s, wherein the polypeptide is characterized by the formula:
- “
P-N-[DE](2)-[YX1X2X3]-[DE](1,2)-[YX1X2X3]-[DE]-[YX1X2X3]-[DE](1,2),”
where amino acid residues in square brackets indicate alternative amino acids, numbers in parentheses indicate the number of amino acid residues, such that [DE](2) represents DD, EE, DE, or ED;
“
X1”
represents Phe-(p-CH2)SO3H, “
X2”
represents sulfated tyrosine, and “
X3”
represents 2-sulfotyrosine (SEQ ID NO;
127). - View Dependent Claims (2, 3, 4, 18, 20, 22)
- “
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5. A polypeptide that inhibits complement C1s, wherein the polypeptide comprises an amino acid sequence that is characterized by the formula:
- “
[AP]-N-[DE](2)-[X1X2X3]-[DE](1,2)-[X1X2X3]-[DE]-[X1X2X3]-[DE](1,2)”
where amino acid residues in square brackets indicate alternative amino acids, numbers in parentheses indicate the number of amino acid residues, such that [DE](2) represents DD, EE, DE, or ED;
“
X1”
represents Phe-(p-CH2)SO3H, “
X2”
represents sulfated tyrosine, and “
X3”
represents 2-sulfotyrosine (SEQ ID NO;
126).
- “
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6. A peptide or polypeptide that inhibits complement C1s, wherein the peptide or polypeptide comprises the amino acid sequence “
- CRLGC”
(amino acid residues 64 to 68 of SEQ ID NO;
1), wherein the peptide or polypeptide consists of five to thirty amino acid residues. - View Dependent Claims (7, 8)
- CRLGC”
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9. A complement C1s inhibitor, wherein the inhibitor consists of:
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(a) a C1s catalytic site-directed moiety (CCSDM), which is selected from the group consisting of;
(i) CH3-Lys(Cbo)-Gly-Arg-pNA-AcOH, where “
Cbo”
represents benzyloxycarbonyl;
(ii) CH3-Lys(Cbo)-Gly-Arg;
(iii) H-D-Val-Ser-Arg-pNA•
HCl;
(iv) H-D-Val-Ser-Arg;
(v) Leu-Xaa-Arg, where “
Xaa”
represents alanine, glutamine, or glycine;
(vi) LQRALEILPN RVTIKANRPF LVFI (SEQ ID NO;
118), (vii) serine protease inhibitor;
(viii) heterocyclic protease inhibitor;
(ix) transition state analogue;
(x) benzamidine;
(xi) X-C1-C2-A-Y, where C1 is a derivative of Arg, Lys, or Orn, characterized by a reduced carboxylate moiety or a carboxylate moiety that is displaced from the α
-carbon by a chemical structure characterized by a backbone chain of from 1 to 10 atoms, C2 is a non-cleavable bond, “
X”
is hydrogen or a continuation of the peptide backbone, “
A”
is a backbone chain, and “
Y”
is a bond;
(xii) CDGFK CRLGC TYGFK TDKKG CEAFC TCNT (SEQ ID NO;
121); and
(xiii) X-C-X(8-12)-L-Q-R, where “
X”
represents glycine, serine, or threonine, and numbers in parentheses indicate the number of amino acid residues (SEQ ID NO;
140);
(b) a linker moiety that is either characterized by a backbone chain having a calculated length of between 14 Å and
20 Å
, or that is a polypeptide, which has the amino acid sequence of KETAC VNIWC TDPYK CNPES GRCED (SEQ ID NO;
123); and
(c) a C1s exosite binding moiety (CEBM), which is selected from the group consisting of;
(i) a polypeptide characterized by the formula;
“
[AP]-N-[DE](2)-[YX1X2X3]-[DE](2)-[YX1X2X3]-[DE]-[YX1X2X3]-[DE](1,2),”
where amino acid residues in square brackets indicate acceptable amino acids, numbers in parentheses indicate the number of amino acid residues, “
X1”
represents Phe-(p-CH2)SO3H, “
X2”
represents sulfated tyrosine, and “
X3”
represents 2-sulfotyrosine (SEQ ID NO;
126); and
(ii) NEDYEDYEYD (SEQ ID NO;
119);
wherein the C1s catalytic site-directed moiety is bound to the linker moiety, the linker moiety is bound to the C1s exosite binding moiety. - View Dependent Claims (11, 12, 13, 14, 15)
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10. (canceled)
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16. A complement C1s inhibitor, wherein the inhibitor consists of:
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(a) a C1s catalytic site-directed moiety (CCSDM), which is selected from the group consisting of;
(i) GCDGFKCRLG CTYGFKTDKK GCEAFCTCNT (SEQ ID NO;
53); and
(ii) CRLGC (amino acid residues 64 to 68 of SEQ ID NO;
1);
(b) a linker moiety characterized by a backbone chain having a calculated length of between 14 Å and
20 Å
; and
(c) a C1s exosite binding moiety (CEBM), which is a polypeptide characterized by the formula;
“
A-N-[DE](2)-[YX1X2X3]-[DE](2)-[YX1X2X3]-[DE]-[YX1X2X3]-[DE](1,2),”
where amino acid residues in square brackets indicate acceptable amino acids, numbers in parentheses indicate the number of amino acid residues, “
X1”
represents Phe-(p-CH2)SO3H, “
X2”
represents sulfated tyrosine, “
X3”
represents 2-sulfotyrosine (SEQ ID NO;
128);
wherein the C1s catalytic site-directed moiety is bound to the linker moiety, the linker moiety is bound to the C1s exosite binding moiety. - View Dependent Claims (17, 19, 21, 23)
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Specification