Arg-Gly-Asp (RGD) Peptides and Peptidomimetics as Therapeutics: Relevance for Renal Diseases

Abstract

Cells interact with the extracellular matrix and other cells via cell adhesion receptors which include those of the integrin family. Since the pivotal demonstration in 1984 by Pierschbacher and Ruoslahti that cell adhesion mediated by fibronectin could be inhibited by the simple tripeptide, Arg-Gly-Asp (RGD), then number of other peptide sequences have been shown to recapitulate integrin-ligand interactions. Similarly, the function of integrins in normal renal development and physiology and changes in adhesion receptor expression in diseases, such as glomerulonephritis or renal carcinoma, have suggested that abnormal integrin function in the kidney could be susceptible to modification by integrin antagonists. This possibility has been tested in experimental acute renal failure with ‘RGD peptides’ and in modifying renal tranpslant rejection in patients by use of antibodies to various leucocyte or endothelial cell adhesion molecules. The recent development of a number of orally active, non-peptidic integrin antagonists suggests that treatment of a range of renal diseases may be susceptible to strategies that involve the blockade of integrin function or modulation of their expression.

Cyclic arginine-glycine-aspartic acid peptide inhibits macrophage infiltration of the kidney and carotid artery lesions in apo-E-deficient mice

“…Our findings extend the previous usage of RGD peptides in blocking cell-to-matrix adhesion, inhibiting angiogenesis and platelet aggregation, and as probes for imaging of vascular injury (4,6,10,21,23) and raise the possibility of their therapeutic applicability in suppressing monocytic infiltration of the vascular wall, the prerequisite for the formation of atherosclerotic plaque, especially in the vessels with intimal injury and in renal microcirculation. Therefore, our observation on the potency of cRGD peptide in inhibiting monocyte-endothelial cell interaction makes this nontoxic and nonimmunogenic compound an attractive alternative to the neutralizing antibodies.…”

Plexin D1 Expression Is Induced on Tumor Vasculature and Tumor Cells: A Novel Target for Diagnosis and Therapy?

“…An alternatively spliced fibronectin molecule is deposited in the basement membrane of newly formed vessels, and single-chain antibodies against this protein have been successfully used to detect clinical tumors in whole body scintigraphs (16). RGD motif containing peptides have been used to target integrin a v h 3 (37,38), resulting in endothelial apoptosis and antitumor activity in animal models, but expression of this integrin is restricted to early stages of angiogenesis. Because mature tumor vessels may therefore be less sensitive to such targeting, it may be more relevant to identify target markers that fulfil the prerequisite of being expressed in mature human tumors.…”

Successful Targeting to Rat Hepatic Stellate Cells Using Albumin Modified with Cyclic Peptides That Recognize the Collagen Type VI Receptor

“…Studies on drug carriers to the platelet-derived growth factor receptor are in progress. The targeting to receptors that are up-regulated on the activated fibrogenic cells in pathological processes may also be applicable for targeting of therapeutic agents to other fibrogenic processes, such as atherosclerosis or glomerulosclerosis (54).…”