B7-33 is a synthetic peptide derived from the B-chain of H2-relaxin (also known simply as relaxin-2). It has emerged as a functionally selective agonist for the relaxin family peptide receptor 1 (RXFP1), with characteristics that differ from the parent molecule in both structure and signalling profile. Research indicates that B7-33 might offer helpful tools for investigating fibrotic, vascular, cardiac, renal, and potentially pulmonary processes in laboratory settings. This article reviews what is known about B7-33, what its unique properties may be, and how it might be relevant in various research domains.
Structural Features and Receptor Interaction
1. Origin and design: B7-33 consists of residues 7-29 of the B-chain of H2-relaxin, extended by a four-residue tail (KRSL) drawn from the B1-33 isoform to improve solubility. This makes B7-33 a single-chain peptidomimetic rather than the two-chain, three disulfide bond structure of full relaxin-2.
2. Solubility and synthesis: Because of its simpler single-chain structure, B7-33 appears easier and cheaper to synthesise, and more soluble than certain truncated or modified relaxin constructs.
3. Affinity and selectivity: Investigations suggest B7-33 may bind specifically to RXFP1, with little or no activation of RXFP2 observed. However, its binding affinity to RXFP1 is lower relative to full H2-relaxin in overexpressing cell lines. Despite this, in endogenous cells (e.g., fibroblasts expressing RXFP1 endogenously), its potency in some functional assays appears comparable to H2-relaxin.
4. Biased signalling: A key distinguishing property of B7-33 is its signalling bias: it seems to activate the ERK1/2 (extracellular signal-regulated kinase) pathway preferentially rather than triggering high levels of cyclic adenosine monophosphate (cAMP)-mediated signalling. This bias may underlie some of its differing behaviour compared to relaxin-2.
Functional Properties Speculated in Research Models
Anti-Fibrosis and Tissue Remodelling
5. Fibrosis in cardiovascular and lung models: Research indicates that B7-33 may reverse or reduce fibrotic changes in several organ systems in experimental models. In cardiovascular models, B7-33 appears to reduce interstitial collagen deposition, modulate fibroblast activity, and limit adverse remodeling.
6. Mechanisms linked to matrix metalloproteinases (MMPs): Studies suggest that B7-33 might increase expression or activation of MMP-2 (matrix metalloproteinase-2), which participates in the degradation of extracellular collagen matrices. Such modulation of extracellular matrix turnover might underlie its anti-fibrotic potential.
7. Signalling interaction with TGF-β and inflammatory pathways: In research models involving cardiac stressors, B7-33 appears to reduce markers of transforming growth factor-β1 (TGF-β1) expression, decrease accumulation of myofibroblasts, and limit macrophage infiltration in cardiac tissue. These findings suggest that B7-33 might modulate both fibrogenic and inflammatory signals in settings of injury or remodeling.
Cardioprotection and Stress Response
8. Protection against ischemia-reperfusion injury or simulated injury: Research indicates that in cardiomyocytes exposed to simulated ischemia-reoxygenation (SIRO) or related stress, B7-33 might reduce markers of cell death or stress, such as reduced expression of GRP78 (an ER stress marker) and ASC (an apoptosis-associated protein). It is also believed to promote the survival of cells under such stress. These speculations suggest B7-33 might mitigate cell death or maladaptive stress pathways under injury.
9. Preservation of cardiac structure and function: In research models of myocardial infarction or other cardiac damage, B7-33 has been hypothesized to limit infarct size, preserve fractional shortening, and reduce adverse remodeling. These properties suggest that the peptide might have relevance in investigating mechanisms of cardiac repair and remodeling.
Vascular Function and Endothelial Research
10. Vasoprotection: B7-33 appears to replicate certain vascular properties of relaxin, particularly in mesenteric arteries, where it may support bradykinin-mediated, endothelium-dependent relaxation via endothelium-derived hyperpolarization. However, in some vascular beds (e.g., aorta or small renal arteries), its activity is thought to be weaker or more limited.
11. Endothelial dysfunction models: In some experimental setups, B7-33 seems to prevent or attenuate endothelial dysfunction induced by pathological factors (e.g., trophoblast conditioned media in the context of preeclampsia-like). That suggests potential relevance for studying how RXFP1 agonism might restore or protect endothelial cell function.
Renal and Other Organ System Investigations
12. Renal fibrosis and renal myofibroblasts: In cells derived from renal tissue, especially myofibroblasts with endogenous RXFP1 expression, B7-33 has been suggested to activate ERK1/2 at levels similar to H2-relaxin and also stimulate MMP-2-mediated collagen degradation. These findings imply that B7-33 might be relevant for investigating mechanisms of chronic kidney disease, fibrosis progression, and repair.
13. Pulmonary research: While more limited, there is an indication in lung fibrosis models that B7-33 might reduce fibrotic burden, possibly similar to effects in the heart, offering a tool for studying pulmonary fibrosis and extracellular matrix regulation in lung tissue.
Summary
B7-33 is a promising peptide analog derived from relaxin-2, designed to be simpler in structure (single chain), with better-supported solubility, and a biased signalling profile favouring ERK1/2 activation over strong cAMP stimulation. In research models, it has been suggested that:
14. It may reduce fibrosis (heart, lung, kidney) via modulation of extracellular matrix turnover, MMP expression, and reduction of collagen accumulation.
15. It may protect cardiac tissues under stress (preserving structure and function in infarct or simulated injury)
16. It may modulate vascular function and endothelial responses, including reversing or preventing endothelial dysfunction.
17. It may rescue angiogenic balance in cytotrophoblast models under anti-angiogenic or hyperglycemic stress.
Given these properties, B7-33 may be a valuable tool in the mechanistic research of fibrosis, regeneration, repair, angiogenesis, and cardiovascular biology. Key areas for further investigation include supporting its stability in experimental systems, mapping signalling and functional endpoints more thoroughly, dissecting receptor interactions and structural determinants of its binding, and comparative analyses with other relaxin family peptides or mimetics. Click here to learn more about the potential of this compound.
References
[i] Hossain, M. A., Vredegreef, C., Cadman, R., Bathgate, R. A. D., & Jans, D. A. (2016). A single-chain derivative of the relaxin hormone is a functionally selective agonist of RXFP1.Chemical Science, 7(2), 1189-1201. https://doi.org/10.1039/c5sc04754d
[ii] Devarakonda, T., Mauro, A. G., Guzman, G., Hovsepian, S., Cain, C., Das, A., … Salloum, F. N. (2020). B7-33, a functionally selective relaxin receptor 1 agonist, attenuates myocardial infarction-related adverse cardiac remodeling in mice. Journal of the American Heart Association, 9(8), e015748. https://doi.org/10.1161/JAHA.119.015748
[iii] Handley, T. N. G., Alam, F., Praveen, P., Hossain, M. A., Bathgate, R. A. D., & other authors. (2023). Further developments towards a minimal potent derivative of H2 relaxin: structure–activity relationships of B7-33 analogues. Journal of Medicinal Chemistry. Advance online publication. https://doi.org/10.1021/acs.jmedchem.4c03085
[iv] Praveen, P., Alam, F., Handley, T. N. G., & Hossain, M. A. (2023). A lipidated single-B-chain derivative of relaxin exhibits prolonged activity and improved pharmacokinetics. International Journal of Molecular Sciences, 24(7), 6616. https://doi.org/10.3390/ijms24076616
[v] Samuel, C. S., & Finch-Whiting, S. (2022). Relaxin as an anti-fibrotic treatment: recent advances & future directions. Biochemical Pharmacology, 197, 114928. https://doi.org/10.1016/j.bcp.2021.114928
