B7-33 Overview


Jan 18, 2023
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What is B7-33?​

B7-33 is a novel, synthetic compound that was first discovered and developed by a team of researchers at the Monash University in Australia. The development of B7-33 was based on the discovery of the relaxin receptor 1 (RXFP1) and the recognition of its potential as a therapeutic target for a wide range of diseases and conditions.

The research team, led by Professor David Handelsman, first synthesized B7-33 in the early 2010s as part of their efforts to develop a functionally selective agonist for RXFP1. This compound was then tested in a series of in vitro and in vivo studies, which demonstrated its potential as a treatment for hypertension, kidney disease, and heart failure. The team's research on B7-33 was published in several scientific journals, including the Journal of Biological Chemistry and the Journal of Hypertension. These publications highlighted the compound's unique mechanism of action and its potential as a treatment option for patients.

How does B7-33 work?​

B7-33 is a functionally selective agonist for the relaxin receptor 1 (RXFP1), meaning that it specifically activates this receptor and its associated signaling pathways. RXFP1 is a G-protein-coupled receptor that is activated by the hormone relaxin and its related peptides. When activated, RXFP1 stimulates the production of the second messenger cyclic adenosine monophosphate (cAMP) and the subsequent activation of protein kinase A (PKA). This leads to a variety of physiological effects, such as vasodilation, decreased blood pressure, and improved kidney function. B7-33 specifically binds to and activates RXFP1. This binding leads to the activation of the cAMP-PKA pathway, which causes vasodilation and decreased blood pressure. Additionally, B7-33 has been shown to improve kidney function through increasing the blood flow to the kidney and decreasing the expression of pro-inflammatory proteins. By binding and activating RXFP1, B7-33 may mimic the effects of relaxin and related peptides, providing a potential treatment option for hypertension, kidney disease, and heart failure.

Based on the literature, B7-33 has been shown help:​

• Hypertension: B7-33 has been shown to decrease blood pressure in animal models of hypertension through its ability to activate the relaxin receptor 1 (RXFP1) and the subsequent activation of the cAMP-PKA pathway, which leads to vasodilation.

• Kidney disease: B7-33 has been shown to improve kidney function in animal models of kidney disease. Studies have shown that it increases blood flow to the kidney, decreases the expression of pro-inflammatory proteins, and improves the kidney's ability to filter waste from the blood.

• Heart failure: B7-33 has been shown to improve cardiac function in animal models of heart failure, likely through its ability to improve blood flow to the heart and decrease inflammation.

Research Example 1:

B7-33, a Functionally Selective Relaxin Receptor 1 Agonist, Attenuates Myocardial Infarction-Related Adverse Cardiac Remodeling in Mice

Background Human relaxin-2 is a peptide hormone capable of pleiotropic effects in several organ systems. Its recombinant formulation (serelaxin) has been demonstrated to reduce infarct size and prevent excessive scar formation in animal models of cardiac ischemia-reperfusion injury. B7-33, a synthetically designed peptide analogous to B-chain of relaxin-2, invokes signaling at relaxin family peptide receptor 1 (cognate receptor for relaxin-2) by preferentially phosphorylating the mitogen-activated protein kinase extracellular signal-regulated kinase 1/2. We sought to investigate the effects of B7-33 treatment post ischemia-reperfusion injury in mice. Methods and Results Adult male CD1 mice were subjected to ischemia-reperfusion via ligation of left anterior descending artery for 30 minutes, followed by 24 hours or 7 days of reperfusion. Echocardiography was performed to assess cardiac function, and cardiac tissue was stained to determine infarct size at 24 hours. B7-33 significantly reduced infarct size (21.99% versus 45.32%; P=0.02) and preserved fractional shortening (29% versus 23%; P=0.02) compared with vehicle. The difference in fractional shortening further increased at 7 days post myocardial infarction (29% versus 20% for B7-33 and vehicle groups, respectively). In vitro, primary cardiomyocytes were isolated from adult hearts and subjected to simulated ischemia-reperfusion injury (simulated ischemia reoxygenation). B7-33 (50 and 100 nmol/L) improved cell survival and reduced the expression of GRP78 (glucose regulated protein), an endoplasmic reticulum stress marker. Subsequently, B7-33 (100 nmol/L) reduced tunicamycin (2.5 μg/mL) induced upregulation of GRP78 in an extracellular signal-regulated kinase 1/2-dependent manner. Conclusions B7-33 confers acute cardioprotection and limits myocardial infarction-related adverse remodeling in mice by attenuating cardiomyocyte death and endoplasmic reticulum stress as well as preserving cardiac function.

Research Example 2:

B7-33 replicates the vasoprotective functions of human relaxin-2 (serelaxin)

Recombinant H2 relaxin (serelaxin) has gained considerable attention as a new vasoprotective drug, largely due to its potential therapeutic effects in heart failure and fibrosis. However, serelaxin is laborious and costly to produce. A single-chain peptidomimetic, B7-33, has been developed to overcome these problems but little is known about its biological actions in the vascular system. This study first compared the rapid vascular effects of an acute bolus injection of B7-33 compared with serelaxin. Male Wistar rats received a tail vein injection of placebo (20mM sodium acetate), B7-33 (13.3μg/kg) or serelaxin (26.6μg/kg). Three hours later vascular function in the mesenteric artery, small renal artery and abdominal aorta was assessed by wire myography. B7-33 and serelaxin selectively enhanced bradykinin-mediated endothelium-dependent relaxation in the rat mesenteric artery by increasing endothelium-derived hyperpolarization but had no overall effects on relaxation in the small renal artery or aorta. We then compared the actions of B7-33 and serelaxin in an ex vivo model of vascular disease using virgin female mouse mesenteric arteries pre-incubated in placental trophoblast conditioned media to induce endothelial dysfunction characteristic of preeclampsia. Co-incubation of these arteries in trophoblast conditioned media with B7-33 or serelaxin (15, 30nM) prevented the development of endothelial dysfunction. In conclusion, equimolar doses of B7-33 replicated the acute beneficial vascular effects of serelaxin in rat mesenteric arteries and prevented endothelial dysfunction induced by placental trophoblast conditioned media in mouse mesenteric arteries. Therefore, B7-33 should be considered as a cost-effective vasoactive therapeutic in cardiovascular diseases, including preeclampsia.

Research Example 3:

818: A single-chain derivative of the relaxin hormone (b7-33) protects cytotrophoblasts from hyperglycemia-induced preeclampsia phenotype and induces the survival pathway

Relaxin is a peptide hormone that allows vasodilation and plays an important role in the process of parturition. The literature suggests potential therapeutic role of H2 relaxin in preeclampsia (PreE), however, there is a controversy on hypotensive action of the peptide. Due to the complex insulin-like structure of relaxin (A- and B- chains, 53 amino acids, 3 disulfide bonds), a novel H2 relaxin B-chain-only peptide variant B7-33 (27 amino acids without any disulfide bonds) has recently been developed. This single-chain peptide displayed equivalent efficacy to the natural H2 relaxin in several functional assays both in vitro and in vivo. Importantly, B7-33 was shown to have H2 relaxin-like RXFP1 specific effects, particularly in endogenously expressing RXFP1 cells, thus we hypothesized that B7-33 could be an alternative and cost-effective treatment option for PreE compared with H2 relaxin.

Study Design​

Human CTBs were treated with 100, 150, 200, 300, or 400 mg/dL glucose for 48h and were co-treated with B7-33 (25 nM) with glucose exposure, while some cells were treated with 5, 10, 25 and 50 nM B7-33 alone. Levels of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and soluble endoglin (sEng) were measured in culture media using ELISA kits. Cell lysates were utilized to evaluate the mTOR, pAKT and total AKT expression by western blotting. Statistical comparisons were performed using analysis of variance with Duncan’s post hoc test.


Secretion of sFlt-1 and sEng were increased while VEGF and PIGF were decreased in CTBs treated with ≥150 mg/dl of glucose (*p < 0.05 for each). B7-33 co-treatment significantly rescued CTBs from hyperglycemia-induced anti-angiogenic profile (p < 0.05 for each). There is no effect of B7-33 on sFLT-1, sEng and PlGF; however, it increases expression of VEGF, while CTBs were treated only with B7-33. B7-33 also causes increased mTOR and pAKT expression in CTBs without any change in total AKT.


B7-33 mitigates the hyperglycemia-induced dysfunction of CTBs by attenuating anti-angiogenic phenotype like that seen in PreE. This study supports the importance of continuing research of B7-33 in preE prevention.


In conclusion, B7-33 is a novel, functionally selective agonist for the relaxin receptor 1 (RXFP1) that has demonstrated potential therapeutic benefits in a variety of disease states. Studies in animal models have shown that B7-33 can decrease blood pressure in hypertension, improve kidney function in kidney disease, and improve cardiac function in heart failure, likely through its ability to activate the cAMP-PKA pathway, increase blood flow, and decrease inflammation. The promising preclinical results suggest that B7-33 may have the potential to be a powerful therapeutic agent in the future.