Enzymatic activities in chemokine-mediated inflammation
First Claim
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1. A method for identifying an inhibitor of CCR1 activity, comprising:
- (a) contacting protease with a chemokine substrate in the presence of a test compound;
(b) determining the activity of the protease in the presence of the test compound;
(c) comparing the activity of the protease in the presence of the test compound with the activity of the protease in the absence of the test compound;
(d) identifying the test compound as a potential inhibitor of CCR1 activity if the activity of the protease is inhibited in the presence of the test compound.
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Abstract
Truncated chemokines lacking an N-terminal region that activate CCR1 and/or FPRL1 and compositions containing the truncated chemokines are provided. Methods of identifying agents that modulate CCR1 and/or FPRL1 activity either by modulating the production of the truncated chemokines or the ability of the truncated chemokines to activate CCR1 and/or FPRL1 are also disclosed. Methods using the truncated chemokines to inhibit or activate CCR1 and/or FPRL1 mediated biological activities are also disclosed.
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Citations
46 Claims
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1. A method for identifying an inhibitor of CCR1 activity, comprising:
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(a) contacting protease with a chemokine substrate in the presence of a test compound;
(b) determining the activity of the protease in the presence of the test compound;
(c) comparing the activity of the protease in the presence of the test compound with the activity of the protease in the absence of the test compound;
(d) identifying the test compound as a potential inhibitor of CCR1 activity if the activity of the protease is inhibited in the presence of the test compound. - View Dependent Claims (2, 3, 4)
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5. A method for identifying an inhibitor of FPRL1 activity, comprising:
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(a) contacting protease with a chemokine substrate in the presence of a test compound;
(b) determining the activity of the protease in the presence of the test compound;
(c) comparing the activity of the protease in the presence of the test compound with the activity of the protease in the absence of the test compound;
(d) identifying the test compound as a potential inhibitor of FPRL1 activity if the activity of the protease is inhibited in the presence of the test compound. - View Dependent Claims (6, 7, 8)
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- 9. A method for screening for a modulator of CCR1 activity, the method comprising assaying for an activity of a CCR1 receptor in the presence of a CCR1 ligand fragment and a test agent and comparing the activity level in the presence of the test agent with the activity level in the absence of the test agent, wherein a difference in the activity levels is an indication that the test agent is a modulator of the CCR1 activity.
- 12. A method for screening for a modulator of FPRL1 activity, the method comprising assaying for an activity of an FPRL1 receptor in the presence of an FPRL1 ligand fragment and a test agent and comparing the activity level in the presence of the test agent with the activity level in the absence of the test agent, wherein a difference in the activity levels is an indication that the test agent is a modulator of the FPRL1 activity.
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15. A CCR1 ligand analogue, comprising:
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(a) a CCL6 analogue, wherein said CCL6 analogue comprises a CCL6 amino acid sequence in which there is a modification which inhibits cleavage between residues 13 and 27 by a serine protease;
(b) a CCL9 analogue, wherein said CCL9 analogue comprises a CCL9 amino acid sequence in which there is a modification which inhibits cleavage between residues 13 and 26 by a serine protease;
(c) a CCL15 analogue, wherein said CCL15 analogue comprises a CCL15 amino acid sequence in which there is a modification which inhibits cleavage between residues 17 and 32 by a serine protease;
or(d) a CCL23 analogue, wherein said CCL23 analogue comprises a CCL23 amino acid sequence in which there is a modification which inhibits cleavage between residues 17 and 33 by a serine protease. - View Dependent Claims (16)
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- 17. A pharmaceutical composition comprising (i) an inhibitory agent that inhibits a serine protease having capacity to cleave an N-terminal fragment from CCL6, CCL9, CCL15 and/or CCL23 to generate a CCR1 ligand fragment that can activate CCR1, and (2) a pharmaceutically effective carrier.
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21. A pharmaceutical composition comprising (i) an inhibitory agent that inhibits a serine protease having capacity to cleave an N-terminal fragment from CCL23β
- to generate an FPRL1 ligand fragment that can activate FPRL1, and (2) a pharmaceutically effective carrier.
- View Dependent Claims (30, 31)
- 22. A pharmaceutical composition comprising an inhibitory agent that inhibits a CCR1 ligand fragment from binding to CCR1 and a pharmaceutically effective carrier.
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26. A pharmaceutical composition comprising an inhibitory agent that inhibits an FPRL1 ligand fragment from binding to FPRL1 and a pharmaceutically effective carrier.
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32. An isolated polypeptide that is a fragment of CCL6 (SEQ ID NO:
- 1), has at least 90% sequence identity to SEQ ID NO;
2, and can bind CCR1.
- 1), has at least 90% sequence identity to SEQ ID NO;
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33. An isolated polypeptide that (1) is a truncated form of CCL6 (SEQ ID NO:
- 1) in which the N terminal 13-27 amino acids of CCL6 are deleted, and (2) can bind CCR1.
- View Dependent Claims (34, 46)
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35. An isolated polypeptide that is a fragment of CCL9 (SEQ ID NO:
- 4), has at least 90% sequence identity to SEQ ID NO;
5, and can bind CCR1.
- 4), has at least 90% sequence identity to SEQ ID NO;
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36. An isolated polypeptide that (1) is a truncated form of CCL9 (SEQ ID NO:
- 4) in which the N terminal 13-26 amino acids of CCL9 are deleted, and (2) can bind CCR1.
- View Dependent Claims (37)
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38. An isolated polypeptide that is a fragment of CCL15 (SEQ ID NO:
- 9), has at least 90% sequence identity to SEQ ID NO;
10, and can bind CCR1.
- 9), has at least 90% sequence identity to SEQ ID NO;
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39. An isolated polypeptide that (1) is a truncated form of CCL15 (SEQ ID NO:
- 9) in which the N terminal 17-32 amino acids of CCL15 are deleted, and (2) can bind CCR1.
- View Dependent Claims (40)
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41. An isolated polypeptide that is a fragment of CCL23 (SEQ ID NO:
- 16), has at least 90% sequence identity to SEQ ID NO;
17, and can bind CCR1.
- 16), has at least 90% sequence identity to SEQ ID NO;
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42. An isolated polypeptide that (1) is a truncated form of CCL23 (SEQ ID NO:
- 16) in which the N terminal 17-33 amino acids of CCL23 are deleted, and (2) can bind CCR1.
- View Dependent Claims (43)
Specification