US 7,345,020 B2Granted

Mimetics of CD4 that inhibit immune response

AssigneeThomas Jefferson University

InventorsRobert Korngold, Ziwei Huang

Life of this patent

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Abstract

The application concerns a method of identifying compounds that can be used to inhibit undesired human CD4+ T cell immune responses by identifying compounds that block the interaction of CD4 and MHC, class II, gene products and a method of treatment which comprises administering such an identified compound. The compounds that inhibit undesired human CD4+ T cell immune responses can be used to treat disease such as multiple sclerosis and to prevent graft rejection and graft versus host disease. More specifically, the application concerns compounds having molecular weights between about 1400 and 400 that mimic three portions of the human CD4 lymphocyte cell surface antigen. The portions are residues 29-35, the C—C′ loop of the D1 domain; residues 317-323, the C—C′ loop of the D4 domain; and residues 346-353, the CDR3 or FG ridge of the D4 domain of the CD4 molecule. Specific examples of such compounds include cyclic peptides and peptidomimetic.

Claims3

Dependent claims

A macrocyclic peptidomimetic corresponding to a tetrameric, pentameric or hexameric peptide, having a 10-member ring according to the formula:

wherein:
R1 is the α-carbon, amino moiety and side chain of the amino terminal amino acid of a tetrameric peptidomimetic or the amino terminal amino acid and the α-carbon, amine and side chain of the second amino acid of a pentameric or hexameric peptidomimetic;
R2 is the side-chain of the second amino acid of a tetrameric or pentameric peptidomimetic or the side-chain of the third amino acid of a pentameric or hexameric peptidomimetic;
R3 is the side chain of the third amino acid of a tetrameric or pentameric peptidomimetic or the fourth amino acid of a pentameric or hexameric peptidomimetic;
and
R4 and 4−N together are the carboxyl terminal amino acid of a tetrameric or pentameric peptidomimetic, or the carboxyl terminal two amino acids of a pentameric or hexameric peptidomimetic;
and
the sequence of amino acids to which R1 through R4 correspond are selected from the following sequences:
*-N-Q-L-I-+
SEQ ID NO:7
*-N-Q-L-I-K-+
SEQ ID NO:8
*-N-Q-I-K-+
SEQ ID NO:9
*-S-N-Q-L-+
SEQ ID NO:10
*-S-N-Q-L-I-+
SEQ ID NO:11
*-S-N-Q-L-I-K-+
SEQ ID NO:12
*-S-N-Q-I-+
SEQ ID NO:13
*-S-N-Q-I-K-+
SEQ ID NO:14
*-N-S-N-Q-+
SEQ ID NO:15
*-N-S-N-Q-L-+
SEQ ID NO:16
*-N-S-N-Q-L-I-+
SEQ ID NO:17
*-N-S-N-Q-I-K-+
SEQ ID NO:19
*-N-S-N-Q-I-+
SEQ ID NO:1
*-K-N-S-N-+
SEQ ID NO:20
*-K-N-S-N-Q-+
SEQ ID NO:21
*-K-N-S-N-Q-L-+
SEQ ID NO:22
*-K-N-S-N-Q-I-+
SEQ ID NO:2
*-E-N-K-E-+
SEQ ID NO:24
*-E-N-K-E-A-+
SEQ ID NO:25
*-L-E-N-K-+
SEQ ID NO:26
*-L-E-N-K-E-+
SEQ ID NO:27
*-L-E-N-K-E-A-+
SEQ ID NO:28
*-K-L-E-N-K-+
SEQ ID NO:29
*-K-L-E-N-K-E-+
SEQ ID NO:30
*-S-G-Q-V-+
SEQ ID NO:31
*-S-G-Q-V-L-+
SEQ ID NO:32
*-D-S-G-Q-+
SEQ ID NO:33
*-D-S-G-Q-V-+
SEQ ID NO:34
*-D-S-G-Q-V-L-+
SEQ ID NO:35
*-S-D-S-G-Q-+
SEQ ID NO:36
*-S-D-S-G-Q-V-+
SEQ ID NO:37
and
*-L-S-D-S-G-Q-+,
SEQ ID NO:39
wherein * denotes the amino terminal and + the carboxyl terminal.

71 more elements

A method of suppressing a human, CD4 T-cell immune response comprising administering to a subject having a medical condition that is ameliorated by the suppression of a CD4 T-cell mediated immune response, an effective amount of a macrocyclic peptidomimetic corresponding to a tetrameric, pentameric or hexameric peptide, having a 10-member ring according to the formula:

wherein:
R1 is the α-carbon, amino moiety and side chain of the amino terminal amino acid of a tetrameric peptidomimetic or the amino terminal amino acid and the α-carbon, amine and side chain of the second amino acid of a pentameric or hexameric peptidomimetic;
R2 is the side-chain of the second amino acid of a tetrameric or pentameric peptidomimetic or the side-chain of the third amino acid of a pentameric or hexameric peptidomimetic;
R3 is the side chain of the third amino acid of a tetrameric or pentameric peptidomimetic or the fourth amino acid of a pentameric or hexameric peptidomimetic;
and
R4 and 4-N together are the carboxyl terminal amino acid of a tetrameric or pentameric peptidomimetic, or the carboxyl terminal two amino acids of a pentameric or hexameric peptidomimetic;
and
the sequence of amino acids to which R1 through R4 correspond are selected from the following sequences:
*-N-Q-L-I-+
SEQ ID NO:7
*-N-Q-L-I-K-+
SEQ ID NO:8
*-N-Q-I-K-+
SEQ ID NO:9
*-S-N-Q-L-+
SEQ ID NO:10
*-S-N-Q-L-I-+
SEQ ID NO:11
*-S-N-Q-L-I-K-+
SEQ ID NO:12
*-S-N-Q-I-+
SEQ ID NO:13
*-S-N-Q-I-K-+
SEQ ID NO:14
*-N-S-N-Q-+
SEQ ID NO:15
*-N-S-N-Q-L-+
SEQ ID NO:16
*-N-S-N-Q-L-I-+
SEQ ID NO:17
*-N-S-N-Q-I-K-+
SEQ ID NO:19
*-N-S-N-Q-I-+
SEQ ID NO:1
*-K-N-S-N-+
SEQ ID NO:20
*-K-N-S-N-Q-+
SEQ ID NO:21
*-K-N-S-N-Q-L-+
SEQ ID NO:22
*-K-N-S-N-Q-I-+
SEQ ID NO:2
*-E-N-K-E-+
SEQ ID NO:24
*-E-N-K-E-A-+
SEQ ID NO:25
*-L-E-N-K-+
SEQ ID NO:26
*-L-E-N-K-E-+
SEQ ID NO:27
*-L-E-N-K-E-A-+
SEQ ID NO:28
*-K-L-E-N-K-+
SEQ ID NO:29
*-K-L-E-N-K-E-+
SEQ ID NO:30
*-S-G-Q-V-+
SEQ ID NO:31
*-S-G-Q-V-L-+
SEQ ID NO:32
*-D-S-G-Q-+
SEQ ID NO:33
*-D-S-G-Q-V-+
SEQ ID NO:34
*-D-S-G-Q-V-L-+
SEQ ID NO:35
*-S-D-S-G-Q-+
SEQ ID NO:36
*-S-D-S-G-Q-V-+
SEQ ID NO:37
and
*-L-S-D-S-G-Q-+,
SEQ ID NO:39
wherein * denotes the amino terminal and+ the carboxyl terminal.

71 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/841,050Filed 7 May 2004 · division
Priority: 29 Jun 1995
Published: US 2004/0266988 A130 Dec 2004
Granted: 18 Mar 2008
Term ends: Not estimatedThe source records don’t support an estimate.

Classification7 codes

C07K 14/70514
Immunoglobulin superfamily: cd4
A61K 31/395
Heterocyclic compounds: having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
A61K 38/00
Medicinal preparations containing peptides
Y10S 930/27
Peptide or protein sequence: cyclic peptide or cyclic protein

Family

Application60/000,710Us provisional application · filed 29 Jun 1995
Application60/004,034Us provisional application · filed 20 Sep 1995
Application08/672,610Parent of this division · filed 28 Jun 1996
Application09/206,786Parent of this division · filed 7 Dec 1998
US 5,846,933 AParent of this division · filed 8 Dec 1998
US 2004/0266988 A1Pre-grant publication · published 30 Dec 2004
US 6,844,421 B1Parent of this division
US 7,345,020 B2This patent

From the US filing history. Foreign family members aren’t listed.