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The peptide B7-33 represents an intriguing synthetic analog of the more complex endogenous hormone H2‑relaxin, designed to selectively target the receptor RXFP1 (relaxin family peptide receptor 1). The peptide is believed to unlock new avenues in research domains, including fibrosis, vascular biology, extracellular matrix remodeling, and tissue adaptation.

Here, we provide a scientific overview of the peptide’s structural features, receptor interactions, and speculative implications in multiple research fields. The objective is to map current knowledge and highlight promising directions for future research.

Structural and Biochemical Characteristics

B7-33 is a 27‐amino‐acid synthetic peptide derived from the B-chain of H2-relaxin. It is designed as a single-chain construct, avoiding the A-chain/B-chain disulfide-bridged complexity of native relaxin. For example, one commercial source lists the sequence as H-Val‐Ile‐Lys‐Leu‐Ser‐Gly‐Arg‐Glu-Leu-Val-Arg-Ala-Gln-Ile-Ala-Ile-Ser-Gly-Met-Ser-Thr-Trp-Ser‐Lys-Arg‐Ser-Leu-OH. The single-chain format likely affords simpler synthesis and improved solubility relative to the native peptide hormone. The peptide is reported to bind RXFP1 and initiate downstream signaling.

An important feature of B7-33 is its signaling bias: rather than strongly promoting cyclic adenosine monophosphate (cAMP) generation, B7-33 is thought to preferentially promote extracellular signal‐regulated kinase (ERK1/2) phosphorylation (pERK) and matrix metalloproteinase (MMP) production in certain cell types.

For instance, in cardiac fibroblasts and rat renal myofibroblasts, B7-33 was ascertained to produce MMP-2 at levels comparable with H2-relaxin via a pERK pathway, while cAMP activation was minimal. In addition, structure‐activity relationship (SAR) work has indicated that lipidation of B7-33 analogs (fatty acid conjugation) may increase the research half-life from ~6 minutes to ~60 minutes.

Mechanistic Insights and Signaling Pathways

The receptor RXFP1 is a G-protein coupled receptor (GPCR) which, in the context of H2-relaxin, has been implicated in vasodilation, extracellular matrix remodeling, fibroblast inhibition, and pro‐angiogenic signaling. B7-33’s interaction with this receptor suggests multiple potential mechanistic threads for research.

One mechanistic axis is MMP induction. In fibroblasts expressing RXFP1, B7-33 is reported to stimulate MMP-2, which is thought to be implicated in collagen degradation and extracellular matrix turnover. Another axis is the pERK pathway. Unlike the classical cAMP route, B7-33 appears to preferentially trigger ERK1/2 phosphorylation in some models, linking to downstream processes of cell survival, remodeling, and adaptation.

In one cardiac injury model, B7-33 exposure was associated with lower expression of GRP78 (a marker of endoplasmic reticulum stress), reduced apoptosis‐associated speck-like protein (ASC) and Toll‐like receptor 4 (TLR4) mRNA, and preserved myocardial function.

Research Domains and Potential Uses

1. Fibrosis and Extracellular Matrix Remodeling

A central area of interest is fibrosis: the excessive deposition of collagen and extracellular matrix (ECM) components in organs, leading to impaired function. B7-33 has been proposed as a tool in research into fibrotic processes. According to reports, B7-33 seems to reduce interstitial collagen deposition and normalize fibroblast overactivity in cardiac, lung, and renal research models.

Furthermore, coatings releasing B7-33 on implantable devices have been reported to reduce fibrotic capsule thickness around implants by ~49% over six weeks in experimental models. In sum, B7-33 may serve as a mechanistic probe in experiments designed to:

1. Investigate fibroblast to myofibroblast differentiation and how RXFP1 engagement may interact with ECM dynamics.
2. Explore MMP induction and collagen degradation in fibrotic tissues.
3. Examine remodeling of vascular or organ scaffolding post-injury, especially relating to collagen deposition and fibroblast proliferation.

1. Vascular Function and Vasoadaptation

Beyond fibrosis, B7-33 seems to be of utility in vascular biology research. The peptide has been indicated to replicate some of H2-relaxin’s vasoprotective features: in one study, it appeared to have enhanced endothelium-dependent relaxation in mesenteric arteries and improved vascular smooth muscle responsiveness.

Given that RXFP1 activation is implicated in vasodilation, endothelial integrity, and modulation of vascular tone, researchers may deploy B7-33 to probe:

1. The role of RXFP1 in vessel remodeling and adaptation under stress or injury.
2. How biased signaling (ERK vs cAMP) at RXFP1 interacts with endothelial cell phenotype, smooth muscle cell behavior, and vascular reactivity.
3. The interplay between extracellular matrix remodeling and vascular function, especially in settings of elevated mechanical stress or impaired endothelial responsiveness.

1. Cardiovascular Remodeling and Myocardial Research

In the cardiac arena, B7-33 has attracted interest for its potential to modulate post-injury structural adaptation. In a research model of ischemia–reperfusion injury, B7-33 exposure was associated with smaller infarct size, better preservation of left ventricular geometry, and less adverse remodeling relative to control.

Although these findings are experimental, they suggest B7-33 may be a useful tool in experiments aimed at:

1. Understanding how RXFP1 signaling may support cardiomyocyte survival, fibroblast activation, and scar formation.
2. Probing the connection between extracellular matrix dynamics, cardiac compliance, and remodeling post-injury.
3. Investigating whether manipulation of biased GPCR signaling (as with B7-33) may modulate pathways relevant to adaptation or cardiac tissue without full engagement of metabolic cAMP pathways.

1. Regenerative Science and Tissue Remodeling Research

Given the remodeling and ECM‐modulating properties of B7-33, it appears to also hold relevance in regenerative science research. For example, investigations might consider whether B7-33 might support angiogenic responses, scaffold integration, or tissue engineering constructs. Some speculative articles propose that B7-33 may support angiogenesis and endothelial cell behavior.

In tissue engineering research, B7-33 may serve as a tool to probe:

1. How modulation of ECM turnover influences scaffold integration and tissue regeneration.
2. The role of biased GPCR signaling (via RXFP1) in controlling fibroblast‐versus‐regenerative phenotypes.
3. How local release of matrix-remodeling peptides influences cellular infiltration, vascularisation, and mechanical compliance of engineered tissues.

Conclusion

In summary, the peptide B7-33 constitutes a promising research tool for investigating remodeling biology, extracellular matrix turnover, vascular responsiveness, and biomaterial–tissue interactions. Through its selective activation of RXFP1 and biased intracellular signaling favoring pERK and MMP induction over cAMP, B7-33 has been hypothesized to offer a mechanistic lever distinct from the parent relaxin hormone.

While current data remain experimental and oriented toward mechanistic studies rather than deployment, the peptide seems to enable a broad spectrum of experimental inquiries across fibrosis research, cardiovascular adaptation, biomaterials integration, and regenerative tissue science. As scientists continue to refine peptide engineering (e.g., lipidation to prolong half-life) and develop more sophisticated model systems, B7-33’s role in basic and translational biology may expand further. Researchers interested in ECM remodeling, vascular biology, or implant integration may find B7-33 to be a valuable addition to their investigational toolkit. Click here to learn more about the potential of this compound.

References

[i] Hossain, M. M., Layfield, S., Ng, V., et al. (2016). A single-chain derivative of the relaxin hormone, B7-33, is a functionally selective agonist at RXFP1 that preferentially activates pERK over cAMP and prevents organ fibrosis. Chemical Science, 7(3), 1600-1610. https://doi.org/10.1039/c5sc04754d

[ii] Samuel, C. S., Ng, V. H., Hossain, M., Bathgate, R. A. D., & Hewitson, T. D. (2022). The single-chain relaxin mimetic, B7-33, maintains the anti-fibrotic effects of relaxin-2 in vitro and in vivo. European Journal of Pharmacology, 929, 175023. https://doi.org/10.1016/j.ejphar.2022.175023

[iii] Broughton, R. J., Ng, V. H., Hossain, M. M., et al. (2017). B7-33, a functionally selective relaxin receptor1 agonist, attenuates myocardial infarction-related adverse cardiac remodeling in mice. Journal of the American Heart Association, 6(12), e005537. https://doi.org/10.1161/JAHA.119.015748

[iv] Sołtysiak, J., Weiss, T., Hossain, M., et al. (2022). A lipidated single-B-chain derivative of relaxin exhibits improved structure-activity relationship and prolonged in vitro half-life: B7-33 lipid analogs. International Journal of Molecular Sciences, 24(16), 12670. https://doi.org/10.3390/ijms241612670

[v] Brinn, J., Samuel, C. S., & Hewitson, T. D. (2020). Relaxin and extracellular matrix remodeling: mechanisms and emerging directions. Pharmacology & Therapeutics, 210, 107500. https://doi.org/10.1016/j.pharmthera.2020.107500

• Tags
• #B7-33 peptide research
• #RXFP1 signaling
• #fibrosis research
• #vascular biology studies
• #extracellular