Integrins in Drug Targeting-RGD Templates in Toxins

Abstract

Integrins are a family of heterodimeric receptors, which modulate many cellular processes including: growth, death (apoptosis), adhesion, migration, and invasion by activating several signaling pathways. Integrin-binding RGD (arginine-glycine-aspartic acid) is found in several important extracellular matrix proteins which serve as adhesive integrin ligands. The RGD motif has also been found in many toxins from snake venom and other sources that specifically inhibit integrin binding function and serve as potent integrin antagonists, particularly of platelet aggregation and integrin-mediated cell adhesion. Many of these proteins have potential as therapeutic agents which can target integrins directly. Structural and functional studies of several RGD-containing toxins suggest that the inhibitory potency of these proteins lies in subtle positional requirements of the tripeptide RGD at the tip of a flexible loop, a structural feature for binding to integrins. In addition, amino acid residues in this loop in close vicinity to the RGD-motif determine the integrin-binding specificity and selectivity. This review will present a review of integrin structure and function, and of disintegrin structural features responsible for their activity as antagonists of integrin function. The use of integrins in drug targeting and integrins as targets for drug delivery by using the RGD as a template structure will also be discussed.

RGD-FasL Induces Apoptosis in Hepatocellular Carcinoma

“…Such peptides promote cell adhesion when insolubilized onto a surface and inhibit it when presented to cells in solution. As the integrin-mediated cell attachment influences and regulates cell migration, growth, differentiation, and apoptosis, RGD peptides and mimics can be used to probe integrin functions in various biological systems (14). Kuroda K., Miyata K. and others have reported that the rhTNF mutant V29 has potent antitumor activity with reduced toxicity in mice (15), whereas another mutant, RGD-T, showed decreased gastrointestinal toxicity (16).…”

Viral infection and human disease - insights from minimotifs

“…RGD peptides can also be used to treat tumors by targeting toxins, radioactive chemicals, antimitotic drugs, and DNA replication inhibitors to tumors (106)(107)(108)(109)(110)(111)(112)(113). Similarly, tumors and tissues can be visualized using RGD peptide conjugates (109,108,114).…”

Isolation and characterization of four medium-size disintegrins from the venoms of Central American viperid snakes of the genera Atropoides, Bothrops, Cerrophidion and Crotalus

“…The disulfide bonds around the RGD sequence determine the formation of a loop [20,26e29]. Therefore both the amino acids adjacent to the RGD tripeptide and the location of disulfide bonds determine the conformation and, consequently, the affinity of the disintegrin for receptors [15,25,30,31]. RGD disintegrins bind to the aIIbb3 integrin on the platelet membrane, thus inhibiting platelet aggregation [14]; moreover, RGD blocks integrins a 8 b 1 , a 5 b 1 ,a v b 1 and a v b 3 .…”