ARA-290, also called cibinetide, is an 11-amino-acid synthetic peptide modeled on a small surface region of erythropoietin (EPO). It was built to test a specific idea: that EPO’s protective effects on injured tissue run through a different receptor from the one that drives red blood cell production, and that a peptide could reach the first without touching the second.
That premise has made ARA-290 a common reference compound in research on the so-called innate repair receptor, as well as in rodent models of nerve injury and neuropathic pain. This overview explains how the peptide was designed, what the receptor model proposes, the main model systems used, and why the underlying receptor biology is still argued over.
At a glance
- Class: Synthetic 11-amino-acid peptide; nonerythropoietic agonist proposed to act at the EPOR/CD131 heteroreceptor
- Origin: Derived from helix B of EPO by Brines, Cerami and colleagues; described in 2008 as pyroglutamate helix B surface peptide (pHBSP)
- Structure: pGlu-Glu-Gln-Leu-Glu-Arg-Ala-Leu-Asn-Ser-Ser; C51H84N16O21; MW 1257.3 g/mol; CAS 1208243-50-8
- Main research areas: tissue-protective receptor signaling, neuropathic pain and nerve injury models, EPO receptor biology
- Regulatory status: Not approved by the FDA or any other regulator; the WADA Prohibited List covers innate repair receptor agonists as a class under S2
Structure and origin
EPO is a four-helix bundle cytokine. Two of its faces bind the classical EPO receptor homodimer that drives red cell production. Through the early 2000s, Michael Brines, Anthony Cerami and colleagues reported that EPO also protected neurons, heart and kidney in injury models, often at concentrations higher than those needed for blood formation. They proposed that these effects ran through a separate complex in which one EPO receptor chain pairs with the β-common receptor subunit (CD131), the shared signaling chain of the IL-3, IL-5 and GM-CSF receptors (Brines et al., 2004).
To separate the two activities, the group looked at the face of helix B that points into solvent and does not take part in classical receptor binding. Peptides copied from that surface kept tissue-protective activity in cell and rodent models but did not stimulate red cell production (Brines et al., 2008). The 11-residue version with an N-terminal pyroglutamate, which protects the peptide from aminopeptidases, became pHBSP and later ARA-290. Like most short linear peptides, it is cleared rapidly from the circulation, so experimental designs tend to rely on early or repeated exposure rather than steady levels.
Mechanism: what the research shows
In the receptor model, tissue injury and local inflammation increase expression of EPOR and CD131 on stressed cells. Binding of an agonist to the heteroreceptor is proposed to activate JAK2 and downstream pathways, including PI3K/Akt and STAT signaling, which reduce apoptosis and dampen inflammatory cytokine production. Brines and colleagues supported this model with co-immunoprecipitation of EPOR and CD131 in neuronal cells and with experiments in which EPO’s protective effect in a mouse injury model was lost in animals lacking CD131 (Brines et al., 2004). ARA-290 itself was shown to reproduce tissue protection in several rodent injury models without changing hematocrit (Brines et al., 2008).
Key areas of study
Neuropathic pain and nerve injury
The best-developed body of preclinical work is in nerve injury. In rats with spared nerve injury, a standard model of neuropathic pain, short courses of ARA-290 were associated with reductions in mechanical and cold allodynia lasting up to 20 weeks. The same study found suppression of the spinal microglial response, while the astrocyte response did not differ from controls (Swartjes et al., 2014). Those results tied the peptide’s effects to neuroimmune signaling in the spinal cord rather than to simple analgesia.
Separating tissue protection from erythropoiesis
The founding studies remain a reference point for anyone working on EPO derivatives. They argued that tissue protection and blood formation could be pulled apart at the level of receptor structure, and that a small peptide could carry the first activity alone (Brines et al., 2004; Brines et al., 2008). Researchers working on carbamylated EPO and other nonerythropoietic derivatives build on the same framework.
The EPO receptor expression debate
A key test of the model is whether functional EPO receptors exist outside the blood-forming system. Using receptor-specific antibodies and functional assays, Sinclair and colleagues reported that functional EPOR was undetectable in endothelial, cardiac, neuronal and renal cells (Sinclair et al., 2010). Ott and colleagues later reported widespread EPOR expression in brain that increased after injury (Ott et al., 2015). Both papers are routinely cited together, and the disagreement is central to how ARA-290 data are interpreted.
What the evidence does not show
The heteroreceptor model is not universally accepted. Antibody specificity problems have clouded EPOR detection for years, and direct structural evidence for an EPOR/CD131 complex binding ARA-290 is limited. Much of the foundational work comes from a closely connected group of investigators and their collaborators. Rodent pain and injury models vary in how well they predict anything beyond the model itself. ARA-290 has been evaluated in clinical studies by its developer, but it is not an approved drug, and none of that work describes the research material sold here.
Regulatory status
ARA-290 is not approved by the FDA or any other regulator; it has been evaluated in clinical studies by its developer. The World Anti-Doping Agency’s Prohibited List includes “innate repair receptor agonists” as a class under S2; ARA-290 is not named individually. Rogue Compounds sells it as a research reagent only.
Handling and storage in the lab
Lyophilized ARA-290 should be kept sealed and refrigerated at 2–8°C (36–46°F), protected from light. Keep the vial closed until use to limit exposure to moisture.
Sourcing and documentation
Rogue Compounds has ARA-290 made in small batches. Every vial carries a batch number and a QR code that opens the independent U.S. testing lab’s own report for that batch. The same batch COA is posted on the product page and in the COA Library.
View ARA-290 on Rogue Compounds
References
- Brines M, et al. Erythropoietin mediates tissue protection through an erythropoietin and common β-subunit heteroreceptor. Proc Natl Acad Sci USA. 2004;101(41):14907-14912. PMID 15456912
- Brines M, et al. Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Proc Natl Acad Sci USA. 2008;105(31):10925-10930. PMID 18676614
- Swartjes M, et al. ARA 290, a peptide derived from the tertiary structure of erythropoietin, produces long-term relief of neuropathic pain coupled with suppression of the spinal microglia response. Mol Pain. 2014;10:13. PMID 24529189
- Sinclair AM, et al. Functional erythropoietin receptor is undetectable in endothelial, cardiac, neuronal, and renal cells. Blood. 2010;115(21):4264-4272. PMID 20124513
- Ott C, et al. Widespread expression of erythropoietin receptor in brain and its induction by injury. Mol Med. 2015;21(1):803-815. PMID 26349059
Research use only. Rogue Compounds products are sold strictly for laboratory research. They are not for human or veterinary use, and nothing in this article is medical advice. The studies cited here describe published research, not this product or any use of it.