Integrin-binding peptides

Details Integrin-binding peptides Integrin-binding peptides

1997-08-29

2001-01-23

Low, Christopher S. R. (Department: 1653)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

15 to 23 amino acid residues in defined sequence

C530S300000, C530S317000, C530S324000, C530S325000, C530S327000, C530S328000, C530S329000, C530S330000

Reexamination Certificate

active

06177542

ABSTRACT:

BACKGROUND OF THE INVENTION
Integrins are transmembrane &agr;&bgr; heterodimer receptors expressed on a wide variety of cells which are involved in extracellular matrix interactions. There are eight known &bgr; subunits and 14 known &agr; subunits which associate with each other to give at least twenty receptors with different ligand specificities. The ligands for several of the integrins are adhesive extracellular matrix (ECM) proteins such as fibronectin, vitronectin, collagens and laminin.
It is becoming increasingly clear that the ECM influences gene expression and changes in expression of genes encoding matrix proteins alter the composition of the ECM. Integrins appear to mediate messages from the exterior to the interior of the cell, inducing various kinds of changes in gene expression. In this capacity, the integrins control many medically important biological phenomena, such as cell migration in development, tissue repair, cancer cell differentiation, platelet aggregation and homing of immune system cells and neuronal processes to target sites.
Many integrins recognize the amino acid sequence RGD (arginine-glycine-aspartic acid) which is present in fibronection or the other adhesive proteins to which they bind. Peptides and protein fragments containing the RGD sequence can be used to modulate the activities of the RGD-recognizing integrins. While apparently successful drugs and devices have been designed based on the RGD sequence for antithrombotic therapy, wound healing and implant acceptance, a limitation of this approach is that RGD peptides not subject to conformational restraint tend to be nonselective in their integrin binding.
Fibronectin is the only known protein ligand for the &agr;
5
&bgr;
1
integrin. This binding is mediated through an RGD (Arginine-Glycine-Aspartic Acid) sequence. In contrast, the integrins &agr;
v
&bgr;
3
and &agr;
IIb
&bgr;
3
, which also recognize the RGD sequence, are capable of binding many different adhesive proteins.
The &agr;
5
&bgr;
1
integrin is important in promoting the assembly of fibronectin matrix and initiating cell attachment to fibronectin. The &agr;
5
&bgr;
1
integrin also appears to be a crucial integrin mediating migration of cells.
The use of ligands with specificity for the &agr;
5
&bgr;
1
receptor permit modulation and manipulation of cell migration in situations such as wound healing, tissue repair and tumor invasion. Thus, there is a need to develop drug-like ligands that bind effectively and selectively to an individual integrin. This invention satisfies this need by providing novel peptides that have improved affinities and selectivities for integrins, particularly the &agr;
5
&bgr;
1
integrin.
SUMMARY OF THE INVENTION
The present invention provides peptides recognized by fibronectin-binding and vitronectin-binding integrins, and in particular by &agr;
5
&bgr;
1
integrin. These peptides are characterized by their ability to interfere with fibronectin and vitronectin binding to various integrins and to block integrin-mediated cell attachment to extracellular matrix proteins. When immobilized onto a surface, these peptides can promote cell attachment through integrin binding.


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Zhang et al., “The &agr;v&bgr;1 Integrin Functions as a Fibronectin Receptor but does not Support Fibronectin Matrix Assembly and Cell Migration on Fibronectin,”J. Cell Biol., 122:235-242 (1993).

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