US 2003/0144211 A1 · Peptide inhibitors of inflammation mediated by selectins

Abstract

Peptides derived from three regions of the lectin domain of GMP-140 and the related selectins, ELAM-1 and the lymphocyte homing receptor, have been found to inhibit neutrophil adhesion to GMP-140. These and additional peptides have been synthesized, having as their core region portions of the 56-60 amino acid sequence of GMP-140, with residue 1 defined as the N-terminus of the mature protein after the cleavage of the signal peptide. Examples demonstrate the inhibition of the binding of neutrophils to GMP-140 of peptides in concentrations ranging from 5 to 1500 μmol. It has been found that alterations within the core sequence, as well as N-terminal and C-terminal flanking regions, do not result in loss of biological activity. The peptides are useful as diagnostics and, in combination with a suitable pharmaceutical carrier, for clinical applications in the modulation or inhibition of coagulation processes or inflammatory processes.

Claims17

Dependent claims

A peptide inhibiting binding of selectins selected from the group having the formula:

R1—X-A-B—C-D-E-Y—R2 (I)
or a pharmaceutically acceptable acid- or based-addition salt thereof wherein:
A is D- or L-asparagine, D- or L-isoleucine or D- or L-valine;
B is D- or L-asparagine or glycine;
C is D- or L-lysine, D- or L-valine or glycine;
D is D- or L-valine, D- or L-threonine or D- or L-isoleucine;
E is D- or L-tryptophan;
X and Y are linear chains of from 0 to 10 amino acids;
R1 is H (signifying a free N-terminal group), formyl, lower alkyl, aryl, lower alkanoyl, aroyl, alkyloxycarbonyl or aryloxycarbonyl and
R2 is OH (signifying a free C-terminal group) lower alkyl or aryl esters, or NR3R4 where R3 and R4 each selected independently from H, lower alkyl or aryl.

7 more elements

A method for the preparation of peptides of the formula:

R1—X-A-B—C-D-E-Y—R2 (I)
or a pharmaceutically acceptable acid- or based-addition salt thereof wherein:
A is D- or L-asparagine, D- or L-isoleucine or D- or L-valine;
B is D- or L-asparagine or glycine;
C is D- or L-lysine, D- or L-valine or glycine;
D is D- or L-valine, D- or L-threonine or D- or L-isoleucine;
E is D- or L-tryptophan;
X and Y are linear chains of from 0 to 10 amino acids;
R1 is H (signifying a free N-terminal group), formyl, lower alkyl, aryl, lower alkanoyl, aroyl, alkyloxycarbonyl or aryloxycarbonyl and
R2 is OH (signifying a free C-terminal group) lower alkyl or aryl esters, or NR3R4 where R3 and R4 each selected independently from H, lower alkyl or aryl.

7 more elements

A method for modifying binding of a selectin comprising providing a peptide having the formula:

R1—X-A-B—C-D-E-Y—R2 (I)
or a pharmaceutically acceptable acid- or based-addition salt thereof wherein:
A is D- or L-asparagine, D- or L-isoleucine or D- or L-valine;
B is D- or L-asparagine or-glycine;
C is D- or L-lysine, D- or L-valine or glycine;
D is D- or L-valine, D- or L-threonine or D- or L-isoleucine;
E is D- or L-tryptophan;
X and Y are linear chains of from 0 to 10 amino acids;
R1 is H (signifying a free N-terminal group), formyl, lower alkyl, aryl, lower alkanoyl, aroyl, alkyloxycarbonyl or aryloxycarbonyl and
R2 is OH (signifying a free C-terminal group) lower alkyl or aryl esters, or NR3R4 where R3 and R4 each selected independently from H, lower alkyl or aryl.

7 more elements

Dependencies are inferred from the claim text.

Peptide inhibitors of inflammation mediated by selectins

Life of this patent

Peptide inhibitors of inflammation mediated by selectins

Life of this patent

Abstract

Claims17