iRGD is a 9-amino acid cyclic

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A ...

(sequence: CRGDKGPDC) and a

molecular mimicry Molecular mimicry is defined as the theoretical possibility that sequence similarities between foreign and self-peptides are sufficient to result in the cross-activation of autoreactive T or B cells by pathogen-derived peptides. Despite the preva ...

agent that was originally identified in an in vivo screening of

phage display Phage display is a laboratory technique for the study of protein–protein, protein–peptide, and protein– DNA interactions that uses bacteriophages (viruses that infect bacteria) to connect proteins with the genetic information that encodes ...

libraries in tumor-bearing mice. The peptide was able to home to tumor tissues, but in contrast to standard RGD (

Arginylglycylaspartic acid Arginylglycylaspartic acid (RGD) is the most common peptide motif responsible for cell adhesion to the extracellular matrix (ECM), found in species ranging from ''Drosophila'' to humans. Cell adhesion proteins called integrins recognize and bind ...

) peptides, also spread much more extensively into extravascular tumor tissue. It was later identified that this extravasation and transport through extravascular tumor tissue was due to the bifunctional action of the molecule: after the initial RGD-mediated tumor homing, another pharmacological motif is able to manipulate tumor microenvironment, making it temporarily accessible to circulating drugs. This second step is mediated through specific secondary binding to

neuropilin-1 Neuropilin-1 is a protein that in humans is encoded by the ''NRP1'' gene. In humans, the neuropilin 1 gene is located at 10p11.22. This is one of two human neuropilins. Function NRP1 is a membrane-bound coreceptor to a tyrosine kinase recepto ...

receptor, and subsequent activation of a trans-tissue pathway, dubbed the C-end Rule, or CendR pathway. __TOC__

Mechanism of action

The iRGD peptide homes and penetrates tumors through a 3-step process: First, the RGD sequence motif mediates binding to αVβ3 and αVβ5 integrins that are expressed on tumor endothelial cells. Second, upon αV binding, a protease cleavage event is activated, revealing the c-terminal CendR motif (R/KXXR/K) of the peptide. Third, the CendR motif is now able to bind to neuropilin-1, activating an endocytotic/exocytotic transport pathway. The pathway triggered by iRGD can be used for the enhanced transport of coupled and coadministered anti-cancer drugs into tumors.

Uses

iRGD peptide has been shown to increase accumulation and penetration of anticancer drugs into tumors, but not into normal tissues - whether the drug is coupled to the peptide or given together with it. iRGD-mediated increased penetration and anti-cancer efficacy has been demonstrated with a variety of anti-cancer small molecules, nanoparticles and antibodies. A San Diego -based biotech company, Cend Therapeutics Inc., is currently testing iRGD-based therapy called CEND-1 in clinical studies in solid tumor patients. The U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) awarded CEND-1

orphan drug An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment of ...

status in 2019, and

fast track designation Fast track is a designation by the United States Food and Drug Administration (FDA) of an investigational drug for expedited review to facilitate development of drugs that treat a serious or life-threatening condition and fill an unmet medical ...

in 2020.

References

{{Reflist Peptides Cyclic peptides Antineoplastic drugs Experimental cancer drugs Orphan drugs