B7-33
B7-33, single-chain relaxin analogue, H2 relaxin B(7-33), relaxin B-chain peptidomimetic
B7-33 is a truncated, single-chain analogue of human relaxin-2 that acts as a biased agonist at the RXFP1 receptor, preferentially triggering ERK1/2 rather than cAMP signalling. It reproduces relaxin's anti-fibrotic and vasoprotective effects in rodents without promoting tumour growth in the model tested. It has never been given to a human.
Mechanism
Human gene-2 relaxin is an insulin-superfamily hormone: two chains, three disulfide bonds, and a difficult, expensive synthesis. It signals through RXFP1, a leucine-rich-repeat G protein-coupled receptor, activating both cAMP/protein kinase A and ERK1/2 pathways. B7-33 strips this down to residues 7 to 33 of the B chain alone, a single linear 27-residue peptide with no A chain and no disulfides, the two native cysteines replaced by serines to stop the peptide dimerising.
What makes it interesting is that the truncation produced functional selectivity rather than simple weakening. B7-33 binds RXFP1 and preferentially activates ERK1/2 over cAMP in cells expressing the receptor endogenously, making it the first reported biased agonist at this receptor. That bias tracks the therapeutic biology in a useful way. Relaxin's anti-fibrotic action runs through RXFP1 heterodimers with the angiotensin II type 2 receptor, signalling via phosphorylated ERK1/2 and inducing matrix metalloproteinase-2, the collagen-degrading enzyme; the biased agonist preserves that arm. Meanwhile, the strong cAMP signalling of full relaxin has been implicated in tumour-promoting effects, and B7-33 did not promote prostate tumour growth in vivo where relaxin did. This is a well-executed piece of medicinal chemistry, whatever one concludes about its clinical prospects.
What the research shows
Hossain's 2016 paper in Chemical Science reported the design and synthesis, RXFP1 binding, the ERK-over-cAMP bias, and prevention or reversal of organ fibrosis and dysfunction in three separate rodent models of heart and lung disease with potency comparable to full-length relaxin, alongside the absence of prostate tumour promotion. Marshall's 2017 study found that a single intravenous bolus in rats selectively enhanced bradykinin-mediated endothelium-dependent relaxation in the mesenteric artery by increasing endothelium-derived hyperpolarisation, with no effect in small renal artery or aorta, and that co-incubation prevented endothelial dysfunction induced by placental trophoblast conditioned media in mouse mesenteric arteries, a preeclampsia model. Alam's 2023 study used isoprenaline-induced cardiomyopathy in male 129sv mice and compared B7-33 against relaxin and against the ACE inhibitor perindopril: B7-33 and relaxin equivalently reduced left ventricular fibrosis, inflammation and cardiomyocyte hypertrophy and restored vessel density and aortic contractility, while perindopril lowered blood pressure and inflammation but did not reduce fibrosis or hypertrophy. The draft version of this monograph described that paper as showing B7-33 outperforming serelaxin; it does not, and the error is corrected here. Two further papers address the compound's principal liability: Praveen developed a lipidated derivative with improved serum stability, and Handley pursued further minimisation.
The context that matters most is not about B7-33 at all. Serelaxin, the recombinant form of the parent hormone, produced encouraging Phase 2 results in acute heart failure and then failed decisively in RELAX-AHF-2, a large randomised Phase 3 trial published in the New England Journal of Medicine in 2019 that found no effect on cardiovascular death or worsening heart failure. The relaxin pathway therefore has a documented history of not translating from promising early data to clinical benefit. A biased agonist of the same receptor may avoid some of the parent's problems, but it inherits that cautionary record, and nothing about B7-33 has yet been tested in a person.
Evidence assessment
Preclinical only
All published work is cell culture and rodent; no clinical trial of B7-33 is registered on ClinicalTrials.gov for any indication, and no human data of any kind exist.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
A single-chain derivative of the relaxin hormone is a functionally selective agonist of the G protein-coupled receptor, RXFP1 Preclinical only
B7-33 bound RXFP1 and preferentially activated pERK1/2 over cAMP, prevented or reversed fibrosis and organ dysfunction with potency similar to H2 relaxin, and did not promote prostate tumour growth in vivo.
B7-33 replicates the vasoprotective functions of human relaxin-2 (serelaxin) Preclinical only
B7-33 selectively enhanced bradykinin-mediated endothelium-dependent relaxation in rat mesenteric artery via endothelium-derived hyperpolarisation, with no effect in renal artery or aorta, and prevented trophoblast-induced endothelial dysfunction ex vivo.
The single-chain relaxin mimetic, B7-33, maintains the cardioprotective effects of relaxin and more rapidly reduces left ventricular fibrosis compared to perindopril in an experimental model of cardiomyopathy Preclinical only
B7-33 and relaxin equivalently reduced left ventricular fibrosis and normalised inflammation and cardiomyocyte hypertrophy while restoring vessel density and aortic contractility; perindopril lowered systolic blood pressure, inflammation and vascular rarefaction but did not reduce fibrosis or hypertrophy.
A Lipidated Single-B-Chain Derivative of Relaxin Exhibits Improved In Vitro Serum Stability without Altering Activity Preclinical only
Lipidation improved serum stability of the single-chain relaxin derivative without loss of activity, addressing the parent peptide's rapid degradation.
Effects of Serelaxin in Patients with Acute Heart Failure High-quality evidence
Serelaxin did not reduce cardiovascular death or worsening heart failure, despite encouraging Phase 2 results.
Safety
No human data of any kind. In rodents, B7-33 lacked the tumour-promoting effect observed with full-length relaxin in a prostate model, which is a favourable preclinical finding but a narrow one. Relaxin family signalling has broad cardiovascular, renal, reproductive and connective-tissue effects, including cervical ripening and systemic vasodilation, and the long-term consequences of chronically biasing that signalling towards ERK are entirely unknown. Any material obtained outside a research setting is unregulated, and a 27-residue peptide of this kind has meaningful potential for immunogenicity that has never been assessed.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | No MHRA authorisation and no UK clinical trials. Not an authorised medicine; supply for human use would engage the Human Medicines Regulations 2012. |
| United States | Not FDA-approved and not in clinical development. No investigational new drug programme or registered clinical trial exists for B7-33. It is a research compound. |
| WADA (sport) | Not individually named on the Prohibited List. As an unapproved substance it would fall within S0, which prohibits at all times any substance with no current approval by any governmental regulatory health authority for human therapeutic use. |
Questions
No. There are no registered clinical trials of B7-33 on ClinicalTrials.gov for any indication and no published human data of any kind. Every result comes from cell culture and rodent studies, principally from the group at the Florey Institute and Monash University that designed the molecule.
RXFP1 can signal through more than one downstream pathway. Full relaxin activates both cAMP/PKA and ERK1/2. B7-33 preferentially activates ERK1/2 while triggering much less cAMP signalling. Since the anti-fibrotic effect runs through ERK and matrix metalloproteinase-2, while the cAMP arm was implicated in tumour promotion, the bias is deliberate: it aims to keep the wanted effect and drop the unwanted one.
That is the right question to ask. Serelaxin failed the RELAX-AHF-2 trial for acute heart failure, which was a mortality and morbidity endpoint in an acutely ill population. The argument for B7-33 is that its anti-fibrotic indications, its biased signalling and its far cheaper synthesis are all different from what was tested. That argument is reasonable and entirely untested in people. Note also that in the head-to-head mouse work B7-33 matched relaxin rather than beating it; the comparator it outperformed on fibrosis was an ACE inhibitor.
The two cysteines in the native B chain would otherwise pair with the A chain or with each other, causing the single-chain peptide to dimerise and aggregate. Replacing them with serine, which is sterically similar but cannot form disulfides, keeps the peptide monomeric and soluble. This is stated explicitly in the original synthesis paper.