Cibinetide
[CAS# 1208243-50-8]

Identification

• Classification: Biochemical >> Peptide
• Name: Cibinetide
• Synonyms: ARA290; PHBSP; PH-BSP; PH BSP;(4S)-5-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-4-amino-1-[[(2S)-1-[[(1S)-1-carboxy-2-hydroxyethyl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-5-oxo-4-[[(2S)-5-oxopyrrolidine-2-carbonyl]amino]pentanoic acid
• Protein Sequence: XEQLERALNSS
• Molecular Formula: C₅₁H₈₄N₁₆O₂₁
• Molecular Weight: 1257.30
• CAS Registry Number: 1208243-50-8
• SMILES: C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@@H]1CCC(=O)N1

Properties

• Density: 1.6±0.1 g/cm³ Calc.^*
• Solubility: Soluble (DMSO) (Expl.)
• Index of refraction: 1.661 (Calc.)^*, 1.661 (Expl.)

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Discovory and Applicatios

Cibinetide, also known as ARA‑290, is a synthetic peptide derived from the three-dimensional structure of erythropoietin (EPO). It was engineered to retain the tissue-protective properties of erythropoietin without engaging its erythropoietic activity, thereby avoiding the risk of stimulating red blood cell production. The peptide consists of a short sequence of amino acids designed to mimic the part of EPO that interacts with the innate repair receptor (IRR), a heteromeric receptor expressed on various non-hematopoietic cells including endothelial cells, neurons, and epithelial tissues. This receptor mediates anti-inflammatory, anti-apoptotic, and cytoprotective signaling pathways.

The discovery of Cibinetide emerged from research on the protective effects of erythropoietin beyond hematopoiesis. While EPO had shown benefits in models of ischemia, tissue injury, and neuropathy, its clinical application was limited due to risks of thrombosis and hypertension related to elevated hematocrit. Structural analysis identified the helix B surface of EPO as the key domain responsible for tissue protection through the IRR. Researchers synthesized a peptide that reproduced the functional surface without the erythropoietic domain, resulting in Cibinetide.

Preclinical studies demonstrated that Cibinetide exerts broad protective effects in various tissue injury models. In experimental models of ischemia-reperfusion injury, the peptide reduced inflammatory responses, decreased cell apoptosis, and preserved tissue architecture. In models of neuropathic pain and small fiber neuropathy, administration of Cibinetide led to significant improvements in nerve fiber density and functional recovery. These effects were consistently observed without any increase in hematocrit, confirming that the peptide selectively activates tissue-protective pathways.

Clinically, Cibinetide has been investigated in patients with diabetic neuropathy and sarcoidosis-related small fiber neuropathy. In randomized, double-blind studies, patients receiving subcutaneous Cibinetide reported reductions in neuropathic pain and improvements in nerve fiber function compared to placebo. Biomarker analyses indicated decreased inflammatory cytokines and enhanced tissue repair signaling, consistent with its mechanism of action via the IRR. The peptide’s pharmacokinetics support once or twice daily administration, and its safety profile is favorable, with minimal adverse events typically limited to mild injection-site reactions.

Beyond neuropathy, Cibinetide has potential applications in a range of conditions involving tissue injury and inflammation, including cardiovascular ischemia, renal injury, and inflammatory disorders. Its design as a non-erythropoietic analog enables exploration of chronic or repeated dosing without the complications associated with full erythropoietin therapy. The peptide exemplifies a rational design approach in therapeutic peptides, where structural knowledge of protein domains can be leveraged to isolate and enhance desired biological activities while minimizing off-target effects.

In summary, Cibinetide represents a novel class of tissue-protective peptides derived from erythropoietin. It selectively engages the innate repair receptor to mediate anti-inflammatory and cytoprotective effects without stimulating red blood cell production. Its discovery and development highlight the importance of structural biology in drug design, and its demonstrated efficacy in preclinical and clinical studies supports ongoing exploration in neuropathy and other tissue injury-related conditions. The peptide’s favorable safety profile, combined with its targeted mechanism of action, underscores its potential as a therapeutic agent for conditions where tissue protection and repair are critical.

References

Brines M, et al. (2015) ARA 290, a nonerythropoietic peptide engineered from erythropoietin, improves metabolic control and neuropathic symptoms in patients with type 2 diabetes. Molecular Medicine 20 658–666 DOI: 10.2119/molmed.2014.00215

Heij L, et al. (2012) Safety and efficacy of ARA 290 in sarcoidosis patients with symptoms of small fiber neuropathy: a randomized, double‑blind pilot study. Molecular Medicine (2012) 18 1385‑1393 DOI: 10.2119/molmed.2012.00332