ARA-290 is a small peptide derived from the erythropoietin (EPO) helix β structural domain. EPO has long been known to act beyond stimulating erythropoiesis in the bone marrow. This glycoprotein, which is produced in the kidney, has been found to stimulate blood vessel growth, promote cell survival, alter blood pressure, and neuroprotect against diabetic neuropathy.ARA-290 has the neuroprotective and analgesic effects of EPO without stimulating erythropoiesis.1 ARA-290 has completed its Phase II trial and is poised to enter a Phase III trial for a variety of applications in diabetes and autoimmune tuberculosis. nodular disease for various applications. The peptide is currently receiving a lot of attention for its ability to control neuropathic pain, but it is also being investigated as a potential stimulant for chronic diabetic wound repair, an immunomodulatory drug, and a potential treatment for systemic lupus erythematosus. (lupus or systemic lupus erythematosus).
Sequence
H-Pyr-Glu-Gln-Leu-Glu-Arg-Ala-Leu-Asn-Ser-Ser-OH
CAS Number
1208243-50-8
Molecular Formula
C51H84N16O21
Molecular Weight
1257.3
Vascular Health
Retinal ischemia is caused by a variety of disease processes and is the leading cause of blindness in industrialized countries. The ability to protect retinal epithelial cells from injury or to promote their regeneration after injury may go a long way toward reducing the disease burden. Studies in mice have shown that ARA-290 protects endothelial colony-forming cells from destruction by inflammation. By doing so, ARA-290 prolongs cell survival and helps endothelial colony forming cells (ECFC) repair and rebuild blood vessels [2].
Other studies in mice have shown that ARA-290 enhances the proliferation, migration, and longevity of ECFC throughout the vascular system.ARA-290 also appears to enhance the homing ability of ECFC, helping them to better target areas of the vascular system in need of repair. It is hoped that this function will not only help to enhance the role of endogenous ECFC, but also help to improve the ability of transplanted ECFC to repair the vascular system and restore blood flow to ischemic tissues [3]. If successful in ECFC transplantation, ARA-290 could open up a whole new field of medical therapies, allowing for the successful transplantation of functional cells for tissue repair, hormone production, protein construction, and more.
Reduction of inflammatory cytokines
Mouse studies have shown that ARA-290 can promote the survival of transplanted islet cells by inhibiting macrophage activation. Treating diabetes by transplanting healthy insulin-producing islet cells has been the holy grail of endocrinology for many years. Unlike exogenous insulin, islet cells provide more physiologic control over blood glucose, thus greatly reducing common complications even in well-controlled diabetes. Unfortunately, islet cells do not survive long after transplantation, so the procedure was almost abandoned. However, with the development of ARA-290, this may change. Studies in mice have shown that these peptides inhibit inflammatory cytokines such as IL-6, IL-12, and TNF-α, which significantly prolongs the survival of transplanted islet cells [4].
ARA-290’s ability to counteract the normal inflammatory response appears to be mediated by the peptide’s binding to the tissue protective receptor (TPR), which enhances tissue protection and helps to modulate the immune system.EPO also binds to the TPR, but has many cardiovascular and hematopoietic side effects, making it unavailable as a therapeutic approach in many, if not most, cases. By binding to TPR without promoting some of the other effects of EPO, peptides such as ARA-290 help reduce apoptosis and lower levels of harmful inflammatory cytokines. The end result is tissue protection and improved tissue regeneration. Both of these features result in reduced morbidity and mortality, faster wound healing, reduced scar formation, and rapid functional recovery after injury [5].
Tissue protection
Studies in mice have shown that ARA-290 can help promote the survival of transplanted islet cells by inhibiting macrophage activation. For many years, treating diabetes by transplanting healthy insulin-producing islet cells has been the holy grail of endocrinology. Unlike exogenous insulin, islet cells provide more physiologic control over blood glucose, thus greatly reducing common complications even in well-controlled diabetes. Unfortunately, islet cells do not survive long after transplantation, so the procedure was almost abandoned. However, with the development of ARA-290, this may change. Studies in mice have shown that these peptides inhibit inflammatory cytokines such as IL-6, IL-12, and TNF-α, which significantly prolongs the survival of transplanted islet cells [4].
ARA-290’s ability to counteract the normal inflammatory response appears to be mediated by the peptide’s binding to the tissue protective receptor (TPR), which enhances tissue protection and helps to modulate the immune system.EPO also binds to the TPR, but has many cardiovascular and hematopoietic side effects, making it unavailable as a therapeutic approach in many, if not most, cases. By binding to TPR without promoting some of the other effects of EPO, peptides such as ARA-290 help reduce apoptosis and lower levels of harmful inflammatory cytokines. The end result is tissue protection and improved tissue regeneration. These two features result in reduced morbidity and mortality, faster wound healing, reduced scar formation, and rapid functional recovery after injury [5].
Immune system
TPR is expressed on a variety of immune cells, including macrophages, dendritic cells, mast cells, and lymphocytes (especially T cells). There is growing evidence that ARA-290 and similar peptides can bind to the TPR on immune cells and directly affect their function.
For macrophages, ARA-290 stimulates the TPR to significantly reduce the excretion of pro-inflammatory cytokines such as TNF-α and IL-6. Interestingly, although downregulation of the immune response leads to reduced pathogen clearance in some cases, it decreases the severity of the disease and helps prevent the onset of long-term disease processes. It has also been shown that activation of the TPR restricts macrophage chemokine secretion pathways, thereby reducing infiltration of inflammatory cytokines while promoting recruitment of tissue macrophages (resident macrophages) to the area of injury. The end result appears to be improved tissue healing and reduced inflammatory side effects.
Other research suggests that ARA-290 may help to alter antigen presentation by dendritic cells, thereby altering adaptive immunity and thus long-term resistance to pathogens to which the body has been exposed. While this may sound like a very bad thing, it is important to remember that adaptive immunity is a major driver of organ and tissue rejection after transplantation. The ability to regulate and fine-tune this process helps to minimize rejection of grafts ranging from kidney and heart transplants to bone marrow transplants and experimental transplants [5], [6].
Immune system modulators such as ARA-290 have multiple applications. Perhaps the most promising is colitis. Colitis can be the result of infection or chronic autoimmune diseases such as Crohn’s disease and ulcerative colitis. Currently, treatment of autoimmune colitis is limited to injectable medications with multiple side effects. The ability to treat colitis with more selective immunomodulators could alleviate the suffering of many patients with inflammatory bowel disease [7].
Another potential avenue for ARA-290’s immunomodulatory effects is the treatment of systemic lupus erythematosus (SLE). Studies in mice have shown that administration of ARA-290 suppresses levels of autoantibodies (i.e., ANA and anti-dsDNA), which are markers for SLE diagnosis and indicators of disease severity. In addition, ARA-290 reduced kidney damage, which often contributes to morbidity and mortality in systemic lupus erythematosus (SLE). These findings suggest that ARA-290 may provide the first truly targeted therapy for SLE [8].
Pain perception
It has long been known that the immune system plays a role in pain perception (injury perception), but effector modulators of this pain mechanism have been difficult to develop. In particular, the immune system plays an important role in the development of neuropathic (nerve-based) pain (e.g., the neuropathies seen in diabetes). Neuropathic pain is known to be difficult to manage, but studies have shown that targeting IRRs (Innate Repair Receptors) can reduce inflammation and alleviate neuropathic pain. ARA-290 is known to act on this receptor, but new research suggests that it also inhibits TRPV1 channel activity. [9].TRPV1 channels, also known as capsaicin receptors, are responsible for sensing heat and associated burning pain, which is frequently reported in neuropathic diseases.ARA-290’s ability to act on this receptor makes it useful for treating pain associated with diabetes, multiple sclerosis, chemotherapy, and amputations.
Loss of small nerve fibers is a result of certain autoimmune diseases, notably tuberculosis and diabetes. Also known as small fiber neuropathy, this condition occurs when the small fibers in the skin responsible for temperature and pain sensation deteriorate. Symptoms vary in severity and can range from a pins-and-needles sensation to the feeling of sand in your shoes or wrinkles in your socks. The pain is usually short-lived but severe and can occur multiple times a day. In the worst cases, the pain can become constant and usually manifests itself as a burning sensation. Studies of patients with small fiber nerve loss have shown that ARA-290 treatment increases the number of small nerve fibers and significantly reduces pain. This suggests that ARA-290 may be effective in treating nerve damage that occurs in conditions such as tuberculosis, diabetes mellitus, thyroid dysfunction, celiac disease, HIV, and other conditions [10], [11].
Orphan drug
In 2016, Araim Pharmaceuticals announced that the FDA granted it orphan drug status to explore the efficacy of daily cipinatide for the treatment of patients with painful tuberous neuropathy. A year later, Chief Scientific Officer Michael Brines, along with several others, published a paper revealing the benefits of ARA-290 in the treatment of peripheral nerve pain and small nerve fiber pain.
According to Dr. Brines and his colleagues, ARA-290 (cibinetide) is being prepared for use in Phase 3 trials for the treatment of neuropathy. This peptide has the potential to treat the approximately 87 million Americans who suffer from nerve damage and its related disorders.ARA-290 even appears to play a role in accelerating the healing of damaged wounds in diabetic mice, suggesting that the peptide may help to avoid the amputations and chronic ulcers that many diabetic patients suffer from in later life [12].
Generalization
While ARA-290 has received much attention for its novel mechanism of controlling neuropathic pain, the peptide has also received attention for its immunomodulatory properties, its ability to stimulate wound repair, and as a potential means of protecting the vascular system during ischemic injury. The most advanced area of research centers around ARA-290’s ability to modulate neuropathic pain. The peptide is currently in Phase II and Phase III trials for the treatment of diabetic neuropathy and nodular neuropathy, respectively. There is also interest in the peptide’s use in the treatment of systemic lupus erythematosus, as well as pain syndromes associated with multiple sclerosis, HIV, celiac disease, and others. There is also growing interest in the use of ARA-290 as a potential disease modifier in inflammatory bowel disease.
ARA-290 has demonstrated minimal side effects, low oral and excellent subcutaneous bioavailability in mice. The dose per kilogram in mice is not intended for humans.ARA-290 is sold by MOL Changes for educational and scientific research only and not for human consumption. Purchase ARA-290 only if you are a licensed researcher.
COA
HPLC
MS
- M. S. Hosseini-Zare, S. Dashti-Khavidaki, M. Mahdavi-Mazdeh, F. Ahmadi, and S. Akrami, “Peripheral neuropathy response to erythropoietin in type 2 diabetic patients with mild to moderate renal failure,” Clin. Neurol. Neurosurg., vol. 114, no. 6, pp. 663–667, Jul. 2012, doi: 10.1016/j.clineuro.2012.01.007.
- O. E. O’Leary et al., “The vasoreparative potential of endothelial colony-forming cells in the ischemic retina is enhanced by cibinetide, a non-hematopoietic erythropoietin mimetic,” Exp. Eye Res., vol. 182, pp. 144–155, 2019, doi: 10.1016/j.exer.2019.03.001.
- G. Hache et al., “ARA290, a Specific Agonist of Erythropoietin/CD131 Heteroreceptor, Improves Circulating Endothelial Progenitors’ Angiogenic Potential and Homing Ability,” Shock Augusta Ga, vol. 46, no. 4, pp. 390–397, 2016, doi: 10.1097/SHK.0000000000000606.
- M. Watanabe et al., “A Nonhematopoietic Erythropoietin Analogue, ARA 290, Inhibits Macrophage Activation and Prevents Damage to Transplanted Islets,” Transplantation, vol. 100, no. 3, pp. 554–562, Mar. 2016, doi: 10.1097/TP.0000000000001026.
- B. Peng, G. Kong, C. Yang, and Y. Ming, “Erythropoietin and its derivatives: from tissue protection to immune regulation,” Cell Death Dis., vol. 11, no. 2, p. 79, Feb. 2020, doi: 10.1038/s41419-020-2276-8.
- L. Yan et al., “EPO Derivative ARA290 Attenuates Early Renal Allograft Injury in Rats by Targeting NF-κB Pathway,” Transplant. Proc., vol. 50, no. 5, pp. 1575–1582, 2018, doi: 10.1016/j.transproceed.2018.03.015.
- M. Nairz et al., “Cibinetide dampens innate immune cell functions thus ameliorating the course of experimental colitis,” Sci. Rep., vol. 7, no. 1, p. 13012, 12 2017, doi: 10.1038/s41598-017-13046-3.
- B. Huang et al., “Non-erythropoietic erythropoietin-derived peptide protects mice from systemic lupus erythematosus,” J. Cell. Mol. Med., vol. 22, no. 7, pp. 3330–3339, 2018, doi: 10.1111/jcmm.13608.
- M. Brines et al., “ARA 290, a nonerythropoietic peptide engineered from erythropoietin, improves metabolic control and neuropathic symptoms in patients with type 2 diabetes,” Mol. Med. Camb. Mass, vol. 20, pp. 658–666, Mar. 2015, doi: 10.2119/molmed.2014.00215.
- D. A. Culver et al., “Cibinetide Improves Corneal Nerve Fiber Abundance in Patients With Sarcoidosis-Associated Small Nerve Fiber Loss and Neuropathic Pain,” Invest. Ophthalmol. Vis. Sci., vol. 58, no. 6, pp. BIO52–BIO60, 01 2017, doi: 10.1167/iovs.16-21291.
- M. van Velzen et al., “ARA 290 for treatment of small fiber neuropathy in sarcoidosis,” Expert Opin. Investig. Drugs, vol. 23, no. 4, pp. 541–550, Apr. 2014, doi: 10.1517/13543784.2014.892072.
- A. Bitto et al., “Activation of the EPOR-β common receptor complex by cibinetide ameliorates impaired wound healing in mice with genetic diabetes,” Biochim. Biophys. Acta BBA – Mol. Basis Dis., vol. 1864, no. 2, pp. 632–639, Feb. 2018, doi: 10.1016/j.bbadis.2017.12.006.
Article/Literature Citation Notes
The purpose of quoting the scientist and professor's article is to acknowledge, recognise and applaud the exhaustive development work that has been done to undertake this peptide research. The scientist does not in any way support or advocate the purchase, sale or use of this product for any reason, and MOL Changes has no affiliation or relationship, implied or otherwise, with the scientist.
warning
These products are intended for scientific purposes only for in vitro research and are not to be used for human, animal or unethical experiments, in vitro research (Latin: in glass) is conducted in vitro. These products are not drugs and are not approved by the Food and Drug Administration in any country for the prevention, treatment or cure of any medical condition, disease or illness. The introduction of this product into humans or animals in any form is strictly prohibited by law.
