B7-33 Peptide – Novel Anti Fibrotic Peptide
Fibrosis is an ailment characterized by the thickening or worsening of tissues. Fibrosis usually occurs when one is suffering through the “end stage” of severe, chronic disorders. While the treatment for fibrosis is variable – ranging from therapy to surgery, it was discovered in 2012 during a clinical trial that a protein called H2-relaxin reduced severe, long-term scarring of the cardiac tissues caused by heart damage (6).
H2-relaxin is a naturally occurring protein and the synthetic analogue of this protein is called B7-33 peptide. Similar to H2-relaxin, B7-33 also possesses anti fibrotic properties over other proven advantages described further below.
Protein and Peptide Background
The H2-relaxin protein found in humans is a class of proteins composed of relaxin, H3-relaxin, insulin like peptide-3 and insulin like peptide-5. All these proteins have proven to show a variety of biological effects including ability to affect genetic functions and affect reproductive, musculoskeletal and cardiovascular systems (2).
There are four different receptors that these relaxin proteins bind with namely RXFP-1, RXFP-2, RXFP-3 and RXFP-4. Each receptor has a different effect in the body, as outlined below (2):
- RXFP-1 receptor is shown to influence sperm movement, improve joint health and play a key role in pregnancy.
- RXFP-2 receptor affects the process of testicular descent.
- RXFP-3 receptor plays a role in sleep disturbances.
- RXFP-4 receptor has shown signs of affecting hunger cycles.
Due to the variety of receptors involved and such a wide range of biological effects, extensive research has been conducted on the protein and its analogues, such as B7-33 peptide, to study their effects in the medical field.
What is B7-33 Peptide
B7-33 is a singular chain peptide, a smaller analogous derivative of the endogenous relaxin protein (3).
Typically, the relaxin peptide is composed of four components – a signal peptide, B chain, C chain, and COOH terminal. Several studies were conducted initially to replicate these peptide structures, however they resulted as being highly insoluble and inactive. After extensive research, scientists modified the structure by producing B chain and elongating the COOH terminal, thereby forming the first ever soluble analogue – B7-33 peptide – in 2016 (3).
Peptide Working Mechanism
Besides the structural difference, the peptide has some other variations from the endogenous proteins, which are rather beneficial than H2-relaxin itself.
B7-33 peptide acts via pERK pathway instead of the cAMP pathway. H2-relaxin traditionally produces its antifibrotic properties via cAMP pathway, which may potentially stimulate the formation of tumors in the body. This is a major side effect of the relaxin treatment (1).
Furthermore, the peptide has a strong affinity towards the RXFP-1 receptors.
The peptide binds with these RXFP-1 receptors, stimulates pERK pathway, which then leads to increased synthesis of MMP-2 matrix metalloproteinase chemicals. These chemicals then inhibit the scarring of the tissues and thereby prevent fibrosis (1).
Biological Uses of B7-33 Peptide
This peptide has demonstrated various advantages in the human medical field, including:
- Possessing antifibrotic properties
- Capability to protect blood vessels
- Helps in treating preeclampsia
- Use as a coating material for body implants
Research and Clinical Studies
Studies Demonstrating Vasoprotective Properties
It was known that H2 relaxin was a potent vasoprotective medication, primarily due to its beneficial effects in combating heart failure and fibrosis. However, due to extensive cost and labor associated in producing H2 relaxin exogenously, it became more important to study and understand whether its analogue B7-33 peptide exhibited the same effects.
This 2017 study (4) was conducted on male wistar rats where their tails were injected with either a placebo (which was sodium acetate), H2 relaxin (dose of 26.6 mcg/kg body weight) or B7-33 (dose of 13.3 mcg/kg body weight). After three hours of administration, these mice were examined for their vascular functions, mainly in the mesenteric artery, renal artery and their abdominal aorta. While the results were not as promising in the renal artery and abdominal aorta, both B7-33 and H2 relaxin showed improved vasodilatory properties in the mesenteric artery.
To understand better, an additional study (4) was carried out in female mice who were experimentally induced with endothelial dysfunction. These mice were then either treated with 15nM B7-33 or 30nM H2 relaxin. Post treatment, it was noticed that both the compounds helped combat and prevent further spread of endothelial dysfunction in mice.
These results prove that B7-33 is able to replicate the exact vasoprotective effects of H2 relaxin and thereby protect blood vessels from further damage. The results also indicate that the peptide may potentially be used in treating certain cardiovascular ailments.
Preeclampsia is a pregnancy ailment characterized by increased hypertension in mothers and decreased fetal weight. This study (5) was conducted to understand the effects of B7-33 peptide in treating pregnant women with preeclampsia.
This was an in vitro study where a human cell culture of cytotrophoblasts (CTBs) was used. Cytotrophoblasts are the cells found in the inner cellular layer of the embryo. These cells were treated with either placebo, or marinobufagenin steroid (at concentrations ranging from 0.1 to 100 nM) or glucose (at doses of 400, 300, 200, 150, or 100 mg/dL) for 2 days. Once treated, some of these cells were then treated with 1 microM dose of relaxin antagonist. All cells were then treated with a 25 nM dose of B7-33 compound.
Upon examination, it was noticed that the cells treated with B7-33 peptide showed an upregulation of the vascular endothelial growth factor, VEGF. Cells that were treated with relaxin antagonists showed reduced VEGF concentration.
These results suggest that the peptide has potent effects on counteracting excessive glucose and marinobufagenin, to combat preeclampsia conditions. Clinical trials are still underway to examine their effects in vivo in humans.
Anti Fibrotic Properties Studies
As mentioned earlier, H2 relaxin is a naturally found protein that helps prevent scarring of the tissues. They mainly function via the cAMP pathway. Studies (6,7) have shown that when treated with a full extended strain of H2 relaxin protein, it induces an increased heart rate and stimulates the spread of carcinogenic cells in the body. This is mainly attributed to its mechanism as it activates cAMP pathway.
Hence, researchers were looking for its derivative that can produce the exact biological effects of anti fibrosis without cAMP activation. The result of their efforts was the B7-33 peptide.
When the peptide was administered in mice that were suffering from myocardial infarction, it resulted in almost 50% reduction in cardiac tissue fibrosis. As a result of this, the heart function improved, leading to fewer complications in the long run. Upon further analysis, it was found that the result was mainly because the peptide increased the concentration of matrix metalloproteinase protein, which counteracted the collagen damaging cells and prevented fibrosis.
Furthermore, a study (1) was also conducted in mice suffering from prostate cancer. These mice were either administered with optimal dose of B7-33 (optimal dose is typically given to exert anti fibrosis) or with higher dose of B7-33 (higher dose than those exerting anti fibrosis effects). Interestingly, at both the doses the effects were the same – that is to prevent the development of fibrosis and also not promote the spread of prostate tumors. This proved that the peptide works exclusively via the pERK pathway and not via cAMP activation, thereby preventing the spread of cancer.
Studies Demonstrating Usage as Coating Material
It is a known fact that the human body is designed to fight against any foreign body entering the system. Typically, the body rejects the foreign item via fibrosis by totally isolating the item and preventing them from causing any dysfunction in the body. This is usually a boon when it comes to antigens and disease causing factors, however, it becomes a problem during body implants. For instance, when implanting a cardiac stent, the body considers this a foreign device and would reject it, leading to serious side effects such as occlusion, and maybe even heart attack.
This may be addressed by coating such medical devices with B7-33 peptide.
In one of the studies (8) conducted, a device was implanted in the mice coated with the peptide to counteract the fibrotic effects of the body. As a result of this peptide release from the device coating, the reduction in device thickness (by fibrosis) was decreased by 49.2% over the 6 week duration of study. While this was only the first step, the results demonstrated promising use of the peptide as coating materials of such medical devices and implants, making them more safe to use in patients.
B7-33 Peptide Side Effects
B7-33 is a comparatively novel peptide and further research and trials are still underway. While there are no known serious adverse effects yet due to the pending studies, it can be expected that some of the side effects will be similar to most other peptides. These include:
- Temporary pain and itchiness at the site of peptide injection
- Dryness of mouth
- Cough, fever, and flu-like symptoms
- Joint pains
B7-33 peptide was first synthesized and its effects discovered in 2016 by researcher M.A Hossain and his team. Since then many studies in mice have been conducted showing promising results of using the peptide as an anti fibrotic agent and has offered the first new means in treating fibrosis and heart failure in nearly two decades.
Currently, no clinical trials have been completed for this peptide and the FDA approval is yet to be granted. This compound is not approved to be used on humans and animals, and is only available for research purposes.
B7-33 peptide is a singular chain derivative of the endogenous H2 relaxin protein found in mammals. The structural difference between the two compounds is that the peptide has an elongated COOH terminal compared to the parent molecule.
There are two major benefits of the peptide over H2 relaxin. One, the peptide functions via pERK pathway and does not cause cAMP activation, thereby not inducing cancer cell spread in the body. Second, the peptide is much easier to produce than H2 relaxin, making it more cost effective.
Besides these benefits, B7-33 also exhibits exceptional anti fibrosis effects in the body which can be useful in treating several cardiovascular and lung disorders. It also possesses vasoprotective properties, making it a promising candidate to treat preeclampsia. Preliminary research so far has shown promising results that the peptide may be used to combat several medical ailments in humans.
(1) Mohammed Akhter Hossain et al, A single-chain derivative of the relaxin hormone is a functionally selective agonist of the G protein-coupled receptor, RXFP1, Drug Discovery Biology Pharmacology Monash Biomedicine Discovery Institute, Vol 7, 2016. https://research.monash.edu/en/publications/a-single-chain-derivative-of-the-relaxin-hormone-is-a-functionall
(2) R J Summers, Recent progress in the understanding of relaxin family peptides and their receptors, British Journal of Pharmacology, Vol 174, issue 10, pg 915-920. https://doi.org/10.1111/bph.13778
(3) Nitin A Patil et al, Relaxin family peptides: structure–activity relationship studies, British Pharmacological Society, vol 174 issue 10, published 06 December 2016. https://doi.org/10.1111/bph.13684
(4) Marshall SA, O’Sullivan K, Ng HH, Bathgate RAD, Parry LJ, Hossain MA, Leo CH. B7-33 replicates the vasoprotective functions of human relaxin-2 (serelaxin). Eur J Pharmacol. 2017 Jul 15;807:190-197. doi: 10.1016/j.ejphar.2017.05.005. Epub 2017 May 3. PMID: 28478069. https://pubmed.ncbi.nlm.nih.gov/28478069/
(5) S.H Afroze et al, Abstract P3042: Novel Peptide B7-33 and It’s Lipidated Derivative Protect Cytotrophoblasts From Preeclampsia Phenotype in a Cellular Model of the Syndrome, 4 Sep 2019. https://doi.org/10.1161/hyp.74.suppl_1.P3042
(6) Silvertown JD, Ng J, Sato T, Summerlee AJ, Medin JA. H2 relaxin overexpression increases in vivo prostate xenograft tumor growth and angiogenesis. Int J Cancer. 2006 Jan 1;118(1):62-73. https://pubmed.ncbi.nlm.nih.gov/16049981
(7) Shu Feng, Irina U. Agoulnik, Natalia V. Bogatcheva, Aparna A. Kamat, Bernard Kwabi-Addo, Rile Li, Gustavo Ayala, Michael M. Ittmann and Alexander I. Agoulnik, Relaxin Promotes Prostate Cancer Progression, March 2007. https://clincancerres.aacrjournals.org/content/13/6/1695
(8) N.Welch et al, Coatings Releasing the Relaxin Peptide Analogue B7-33 Reduce Fibrotic Encapsulation, ACS Applied Materials and Interfaces, Nov 2019. https://www.researchgate.net/publication/337205944_Coatings_Releasing_the_Relaxin_Peptide_Analogue_B7-33_Reduce_Fibrotic_Encapsulation
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